Thiophene and furan 2,5-dicarboxamides useful in the treatment of cancer

ABSTRACT

A novel compound which inhibits certain integrins, particularly α v  integrins. Additionally, the novel compound may be used in a method of treating tumors or cancer which comprises administering a pharmaceutically effective amount of the compound to a patient. Additionally, the novel compound may be used in a method of inhibiting angiogensis. Finally, a method of producing the novel compound is disclosed.

FIELD OF THE INVENTION

[0001] The present invention relates to compounds that inhibit certainintegrins, particularly to compounds that inhibit α_(v) integrins.

BACKGROUND OF THE INVENTION

[0002] Integrins are a major family of adhesion receptors. They areproduced by most cell types and are a means by which the cell senses itsimmediate environnement and responds to changes in extracellular matrix(ECM) composition. ECM is composed of structural and regulatorymolecules, some of which include laminin, collagen, vitronectin andfibronectin, as well as a variety of proteoglycans. These molecules, incooperation with cell surface receptors, not only provide the basis forstructural support, but also contribute to the transmission ofbiochemical signals from the ECM to the cells interior. Thus, integrinsare cell adhesion receptors capable of mediating cell-extracellularmatrix and cell-cell interactions. Integrins are implicated in theregulation of cellular adhesion, migration, invasion, proliferation,angiogenesis, osteoclast bone resorption, apoptosis and gene expression(P. C. Brooks, DN&P, 10(8), 456-61, 1997).

[0003] The integrin family is composed of 15 α and β subunits that arecontained in over twenty different αβ heterodimeric combinations on cellsurfaces. Each heterodimers have distinct cellular and adhesivespecificities. Integrins bind to extracellular matrix proteins or cellsurface molecules through short peptides sequences present in theligands. Although some integrins selectively recognize a singleextracellular matrix protein ligand, other bind to two or more ligands.Several integrins recognize the tripeptide Arg-Gly-Asp (RGD), whereasothers recognize alternative short peptide sequences. Combinations ofdifferent integrins on cell surfaces allow cells to recognize andrespond to a variety of different extracellular matrix proteins (J. A.Varner and D. A. Cheresh, Curr. Opin. Cell Biol., 8, 724-30, 1996).

[0004] The α_(v)-series integrins are a major subfamily of integrins. Aswell as classically mediating cell attachement and spreading, α_(v)integrins are implicated in cell locomotion, in ligand-receptorinternalisation, as virus co-receptors, in management of theextracellular protease cascades and as regulators of tumour progression,angiogenesis and apoptosis. The specificities of the five knownα_(v)-integrins, (α_(v)β₁, α_(v)β₃, α_(v)β₅, α_(v)β₆ and α_(v)β₈ havebeen defined and they exclusively recognize ligands via the tripeptidesequence RGD, including vitronectin (α_(v)β₁, α_(v)β₃, α_(v)β₅),fibronectin (α_(v)β₁, α_(v)β₅, α_(v)β₆), von Willibrand factor(α_(v)β₃), fibrinogen (α_(v)β₃) and osteopontin (α_(v)β₃) (F. Mitjans,J. Cell. Science, 108, 2825-38, 1995).

[0005] In disease, adhesive function is frequently compromised andresults in tissue disorder, aberrant cell migration and dysregulation ofsignaling pathways. It is well known that alterations in the compositionand integrity of the ECM can significantly influence cellular behavior,which in turn may have an impact on a number of pathological processessuch as tumor neovascularization, restenosis, arthritis, tumor growthand metastasis. Thus, inhibiting the function of molecules that regulatethese cellular events may have significant therapeutic benefit (P. C.Brooks, DN&P, 10(8), 456-61, 1997).

[0006] There are at least three major classes of reagents currentlybeing developed as integrin antagonists, and these include antibodies(monoclonal, polyclonal and synthetic) and small synthetic peptides(synthetic cyclic RGD peptides), as well as a family of snakevenom-derived proteins termed “disintegrins”. The third major group ofantagonists includes nonpeptide mimetics and organic-type compounds.

[0007] Integrin α_(v)β₃, the most promiscuous member of the integrinfamily, mediates cellular adhesion to vitronecin, fibronectin,fibrinogen, laminin, collagen, von Willibrand factor, osteopontin andadenovirus penton base. Expression of this integrin enables a given cellto adhere to, migrate on, or respond to almost any matrix protein it mayencounter.

[0008] Integrins of the α_(v) subfamily are implicated in tumourdevelopment. Integrin α_(v)β₃ is minimally, if at all expressed onresting, or normal, blood vessels, but is significantly upregulated onvascular cells within human tumors. In particular, both verticalprogression of the primary melanoma and distant metastases arecharacterized histologically by an increased expression of α_(v)β₃integrin (B. Felding-Habermann et al., J. Clin. Invest., 89, 2018-22,1992). A study involving human malignant melanoma, an increasinglyprevalent and aggressive skin cancer, reported the use of monoclonalantibodies to block the α_(v) integrin-ligand interaction which resultedin severely disrupting the development of the tumor (F. Mitjans et al.,J. Cell Sci., 108, 2825-38, 1995).

[0009] Another important physiological role played by integrin α_(v)β₃in cancer is within the process of angiogenesis. Angiogenesis, theformation of new blood vessels, allows the cancer to spread and grow. Itwas shown that blood vessels involved in angiogenesis have enhancedexpression of α_(v)β₃ (P. C. Brooks et al., Science, 264, 569-571, 1994;C. J. Drake et al., J. Cell Sci., 108, 2655-61, 1995). It was also shownthat preventing the α_(v)β₃ integrin from binding to their ligandscaused apoptosis (programmed cell death) in the endothelial cells ofnewly formed blood vessels and inhibited neovascularization (P. C.Brooks et al., Cell, 79, 1157-64, 1994; M. Christofidou-Solomidou etal., Am. J. Pathol., 151(40), 975-83, 1997; J. Luna, Lab. Invest.,75(4), 563-73, 1996). Thus, antagonists of integrin α_(v)β₃ may providea powerful therapeutic approach ;for the treatment of neoplasia or otherdiseases characterized by angiogenesis.

[0010] Another pathological process which involves α_(v)β₃ is coronaryrestenosis. Surgical trauma and/or injury to blood vessels may lead tothe stimulation of smooth muscle cells resulting in an increasemigration and proliferation of these cells, which causes an occlusion inthe vessel wall and prevents blood flow. Following arterial injury, itwas shown that there was early upregulation of integrin α_(v)β₃ at sitesof cell accumulation within the vessel wall and that selective blockadeof α_(v)β₃ was an effective anti-restenotic strategy (S. S. Srivatsa etal., Cardiovascul. Res., 36, 408-28, 1997).

[0011] α_(v) integrins are especially interesting targets since they areimplicated in many metabolic processes, such as angiogenesis, boneresorption, cellular migration and proliferation. Consequently,antagonists of α_(v) integrins have great therapeutic potential fordiseases such as rheumatoid arthritis, psoriasis, eye diseases (diabeticretinopathy and macular degeneration), restenosis, neointimalhyperplasia, osteoporosis and more particurlarly against tumors, sincethey simultaneously strike at the developing tumor and at its bloodsupply (U.S. Pat. No. 5,843,906-WO 9736859/GD Searle & Co; EP854140/Hoechst AG; WO 9733887-WO9637492/Du Pont Merck Pharm Co; WO9744333-WO 9737655-WO 9532710-WO 9408577).

[0012] There is thus a constant need to find other antagonists of α_(v)integrins in order to provide additional modes of treatments for manydiseases that still have no cure. The present invention satisfies thisand other need.

SUMMARY OF THE INVENTION

[0013] The present invention comprises a novel compound that is aneffective inhibitor of integrins, particularly α_(v) integrins such asα_(v)β₃ and α_(v)β₃. Particularly, the compound is of the followingformula 1:

[0014] wherein X is selected from the group comprising O and S.Furthermore, A₁ and A₂ are individually selected from the groupcomprising O, S and N. G₁ is a C₁₋₄ alkyl chain, and G₃ and G₅ are C₀₋₄alkyl chains. G₂ is selected from the group comprising:

[0015] a C₁₋₄ alkyl-C₆₋₁₀-aryl, or H.

[0016] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. G₄ is a C₅₋₈ aryl, a C₅₋₈arylsulfonylamino, or a C₅₋₈ arylamino. G₆ and G₇ are individuallyselected from the group comprising H, F, Cl, I, Br and a C₁₋₄ alkyl.

[0017] Other embodiments of the present invention include specificcompounds and general formulas disclosed in the detailed descriptionbelow.

[0018] Another aspect of the invention is a process for preparing acompound of formula 1. The method comprises preparing a compoundaccording to Scheme A herein. Other embodiments of the invention includepreparation of compounds according to any of the schemes or processesdisclosed in the detailed description below.

[0019] Another aspect of the present invention includes a method fortreating cancer comprising administering a pharmaceutically effectiveamount of the compound of formula 1 or any compound or formula disclosedin the detailed description to a patient. Other embodiments of theinvention include methods of treatment as set forth in the detaileddescription.

[0020] Yet another aspect of the present invention includes a method fortreating a tumor comprising administering a pharmaceutically effectiveamount of the compound of formula 1 or any compound or formula disclosedin the detailed description to a patient.

[0021] Yet another aspect of the present invention includes a method forinhibiting angiogenesis comprising administering a pharmaceuticallyeffective amount of the compound of formula 1 or any compound or formuladisclosed in the detailed description to a patient.

[0022] Yet another aspect of the present invention includes a method forinhibiting an α_(v) integrin comprising administering a pharmaceuticallyeffective amount of the compound of formula 1 or any compound or formuladisclosed in the detailed description to a patient.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention comprises a novel compound that is andeffective inhibitor of integrins including α_(v) integrins as well as aneffective medicament for the inhibition of angiogenesis and therebytreatment of cancer.

[0024] Particularly, the compound is of formula 1 wherein X is selectedfrom the group comprising O and S. A₁ and A₂ are individually selectedfrom the group comprising O, S and N. G₁ is a C₁₋₄ alkyl chain, and G₃and G₅ are C₀₋₄ alkyl chains. G₂ is selected from the group comprising:

[0025] a C₁₋₄ alkyl C₅₋₈ aryl or H.

[0026] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. G₄ is a C₅₋₈ aryl, a C₅₋₈arylsulfonylamino, or a C₅₋₈ arylamino. G₆ and G₇ are individuallyselected from the group comprising H, F, Cl, I, Br & a C₁₋₄ alkyl.

[0027] In another embodiment, the compound is defined according toformula 1 above except X is S.

[0028] In yet another embodiment, the compound is defined according toformula 1 above except X is O.

[0029] In yet another embodiment, the compound is defined according toformula 1 above except A₁ is a N.

[0030] In yet another embodiment, the compound is defined according toformula 1 above except A₁ is an O.

[0031] In yet another embodiment, the compound is defined according toformula 1 above except A₂ is a N.

[0032] In yet another embodiment, the compound is defined according toformula 1 above except A₂ is an O.

[0033] In yet another embodiment, the compound is defined according toformula 1 above except G₁ is —(CH₂)₀—.

[0034] In yet another embodiment, the compound is defined according toformula 1 above except G₁ is a C₁ alkyl.

[0035] In yet another embodiment, the compound is defined according toformula 1 above except G₁ is C₂ alkyl.

[0036] In yet another embodiment, the compound is defined according toformula 1 above except G₁ is C₃ alkyl.

[0037] In yet another embodiment, the compound is defined according toformula 1 above except G₃ is C₁ alkyl.

[0038] In yet another embodiment, the compound is defined according toformula 1 above except G₃ is C₂ alkyl.

[0039] In yet another embodiment, the compound is defined according toformula 1 above except G₅ is C₁ alkyl

[0040] In yet another embodiment, the compound is defined according toformula 1 above except G₅ is C₂ alkyl.

[0041] In yet another embodiment, the compound is defined according toformula 1 above except G₂ is selected from the group comprising:

[0042] A₃ is selected from the group comprising O and N; A₄ is N.

[0043] In yet another embodiment, the compound is defined according toformula 1 above except G₂ is represented as follows:

[0044] wherein A₃ and A₄ are individually selected from the groupcomprising N or O and G₈ is a C₂₋₃ alkyl. In yet another embodiment, thecompound is defined according to formula 1 above except —N—G₂ forms aguanidino containing moiety.

[0045] In yet another embodiment, the compound is defined according toformula 1 above except —N—G₂ forms a urea containing moiety.

[0046] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is a C₋₈ aryl.

[0047] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is a C₅₋₈ arylsulfonylamino.

[0048] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is an unsubstituted C₅₋₈ arylsulfonylamino.

[0049] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is an unsubstituted C₅₋₈ arylamino.

[0050] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is a substituted C₅₋₈ arylamino.

[0051] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is a substituted phenylsulfonylamino.

[0052] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is phenyl.

[0053] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is an amino pyrimidinyl.

[0054] In yet another embodiment, the compound is defined according toformula 1 above except G₄ is a substituted amino pyrimidinyl.

[0055] In yet another embodiment, the compound is defined according toformula 1 above except G₆ and G₇ are halogens.

[0056] In yet another embodiment, the compound is defined according toformula 1 above except G₆ and G₇ are both fluorine.

[0057] In yet another embodiment, the compound is defined according toformula 1 above except G₆ and G₇ are the same.

[0058] In another embodiment, the compound is defined according to thefollowing formula 2:

[0059] wherein X is S, G₁ and G₃ are C₋₄ alkyl chains and G₄ is selectedfrom the group comprising C₅₋₈ arylsulfonylamino, C₅₋₈ aryl, C₅₋₈arylamino.

[0060] G₂ is represented as follows:

[0061] Particularly, A₃ is selected from the group comprising O, S andN; A₄ is N.

[0062] In another embodiment, the compound is according to formula 2,where X is O or S and G₂ is represented by the formula:

[0063] A₃ is selected from the group comprising O, S and N; A₄ is N. G₈is a C₁₋₄ alkyl chain. Additionally, G₄ is selected from the groupcomprising C₅₋₈ arylsulfonylamino, C₅₋₈ aryl, C₅₋₈ arylamino. G₁ and G₃are C₁₋₄ alkyl chains.

[0064] In another embodiment, the compound is defined according toformula 2 above except X is S.

[0065] In yet another embodiment, the compound is defined according toformula 2 above except X is O.

[0066] In yet another embodiment, the compound is defined according toformula 2 above except A₁ is N.

[0067] In yet another embodiment, the compound is defined according toformula 2 above except A₁ is an O.

[0068] In yet another embodiment, the compound is defined according toformula 2 above except A₂ is a N.

[0069] In yet another embodiment, the compound is defined according toformula 2 above except A₂ is an O.

[0070] In yet another embodiment, the compound is defined according toformula 2 above except G₁ is —(CH₂)₀—.

[0071] In yet another embodiment, the compound is defined according toformula 2 above except G₁ is a C₁ alkyl.

[0072] In yet another embodiment, the compound is defined according toformula 2 above except G₁ is a C₂ alkyl.

[0073] In yet another embodiment, the compound is defined according toformula 2 above except G₁ is a C₃ alkyl.

[0074] In yet another embodiment, the compound is defined according toformula 2 above except G₃ is a C₁ alkyl.

[0075] In yet another embodiment, the compound is defined according toformula 2 above except G₃ is a C₂ alkyl.

[0076] In yet another embodiment, the compound is defined according toformula 2 above except G₈ is a C₁ alkyl.

[0077] In yet another embodiment, the compound is defined according toformula 2 above except G₈ is a C₂ alkyl.

[0078] In yet another embodiment, the compound is defined according toformula 2 above except G₂ is represented as follows:

[0079] wherein A₃ is selected from the group comprising O, S and N andA₄ is N.

[0080] In yet another embodiment, the compound is defined according toformula 2 above except G₂ is represented as follows:

[0081] wherein A₃ and A₄ are individually selected from the groupcomprising N or O and G₈ is a C₂₋₃ alkyl chain.

[0082] In yet another embodiment, the compound is defined according toformula 2 above except —N—G₂ forms a guanidino containing moiety.

[0083] In yet another embodiment, the compound is defined according toformula 2 above except —N—G₂ forms a ureido containing moiety.

[0084] In yet another embodiment, the compound is defined according toformula 2 above except —N—G₂ forms is a cyclic guanidino containingmoiety.

[0085] In yet another embodiment, the compound is defined according toformula 2 above except wherein —N—G₂ forms a cyclic urea containingmoiety.

[0086] In yet another embodiment, the compound is defined according toformula 2 above except G₄ is phenylsulfonylamino.

[0087] In yet another embodiment, the compound is defined according toformula 2 above except G₄ is phenyl.

[0088] In yet another embodiment, the compound is defined according toformula 2 above except G₆ and G₇ are halogens.

[0089] In yet another embodiment, the compound is defined according toformula 2 above except G₆ and G₇ are both fluorine.

[0090] In yet another embodiment, the compound is defined according toformula 2 above except G₆ and G₇ are the same.

[0091] In another embodiment, the compound is represented by thefollowing formula 3:

[0092] wherein G₂ is selected from the group comprising:

[0093] wherein A₃ and A₄ are individually selected from the groupcomprising O, N, or S and G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ isselected from the group comprising O, S and N, A₄ is N G₄ is a C₅₋₈arylsulfonylamino. G₁ and G₃ are C₁₋₄ alkyl chains.

[0094] In another embodiment, the compound is according to the aboveformula 3, wherein G₂ is selected from the group comprising:

[0095] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ is selected from thegroup comprising O, S and N; A₄ is N. G₄ is a C₅₋₈ aryl. G₁ and G₃ areC₁₋₄ alkyl chains.

[0096] In another embodiment, the compound is according to the aboveformula 3, wherein G₂ is selected from the group. comprising:

[0097] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ is selected from thegroup comprising O, S and N; A₄ is N. G₄ is phenylsulfonylamino. G₁ andG₃ are C₁₋₄ alkyl chains.

[0098] In another embodiment, the compound is according to the aboveformula 3, wherein G₂ is selected from the group comprising:

[0099] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ is selected from thegroup comprising O, S and N; A₄ is N. G₄ is an aminopyrimidinyl. G₁ andG₃ are C₁₋₄ alkyl chains.

[0100] In another embodiment, the compound is according to the aboveformula 3, wherein G₂ is selected from the group comprising:

[0101] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ is selected from thegroup comprising O, S and N; A₄ is N. G₄ is selected from the groupcomprising a phenylsulfonylamino, phenyl, or an aminopyrimidinyl.

[0102] In another embodiment, the compound is according to the aboveformula 3, wherein G₂ is selected from the group comprising:

[0103] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain.

[0104] Furthermore, A₃ is selected from the group comprising O, S and N;A₄ is N. G₄ is selected from the group comprising phenylsulfonylamino,aryl, or an aminopyrimidinyl. In another embodiment, the compound isaccording to the above formula 3, wherein G₂ is selected from the groupcomprising:

[0105] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ is selected from thegroup comprising O, S and N; A₄ is N. G₄ is selected from the groupcomprising phenylsulfonylamino, a C₅₋₈ aryl, or an aminopyrimidinyl.

[0106] In another embodiment, the compound is according to the aboveformula 3, wherein G₂ is the following moiety:

[0107] A₃ and A₄ are individually selected from the group comprising O,N, or S. G₈ is a C₁₋₄ alkyl chain. Furthermore, A₃ is selected from thegroup comprising O, S and N; A₄ is N. G₄ is selected from the groupcomprising phenylsulfonylamino, a C₅₋₈ aryl, or an aminopyrimidinyl.

[0108] In another embodiment, the compound is according to formula 3,where G₆ and G₇ are halogens.

[0109] In another embodiment, G₆ and G₇ are the same.

[0110] In yet a more particular aspect of the invention, G₆ and G₇ areboth fluorine.

[0111] In another embodiment, the compound is defined according toformula 3 above except X is S.

[0112] In yet another embodiment, the compound is defined according toformula 1 above except X is O.

[0113] In yet another embodiment, the compound is defined according toformula 3 above except A₁ is a N.

[0114] In yet another embodiment, the compound is defined according toformula 3 above except A₁ is an O.

[0115] In yet another embodiment, the compound is defined according toformula 3 above except A₂ is a N.

[0116] In yet another embodiment, the compound is defined according toformula 3 above except A₂ is an O.

[0117] In yet another embodiment, the compound is defined according toformula 3 above except G₁ is —(CH₂)₀—.

[0118] In yet another embodiment, the compound is defined according toformula 3 above except G₁ is a C₁ alkyl.

[0119] In yet another embodiment, the compound is defined according toformula 3 above except G₁ is a C₂ alkyl.

[0120] In yet another embodiment, the compound is defined according toformula 3 above except G₁ is a C₃ alkyl.

[0121] In yet another embodiment, the compound is defined according toformula 3 above except G₃ is a C₁ alkyl.

[0122] In yet another embodiment, the compound is defined according toformula 3 above except G₃ is a C₂ alkyl.

[0123] In yet another embodiment, the compound is defined according toformula 3 above except G₅ is a C₁ alkyl.

[0124] In yet another embodiment, the compound is defined according toformula 3 above except G₈ is a C₂ alkyl.

[0125] In yet another embodiment, the compound is defined according toformula 3 above except G₂ is selected from the group comprising:

[0126] A₃ is selected from the group comprising O, S and N; A₄ is N.

[0127] In yet another embodiment, the compound is defined according toformula 3 above except G₂ is selected from the group comprising:

[0128] wherein A₃ and A₄ are individually selected from the groupcomprising N or C and G₈ is a C₂₋₃ alkyl chain.

[0129] In yet another embodiment, the compound is defined according toformula 3 above except —N—G₂ forms a guanidino containing moiety.

[0130] In yet another embodiment, the compound is defined according toformula 3 above except —N—G₂ forms a urea containing moiety.

[0131] In yet another embodiment, the compound is defined according toformula 3 above except —N—G₂ forms is a cyclic guanidino containingmoiety.

[0132] In yet another embodiment, the compound is defined according toformula 3 above except wherein —N—G₂ forms a cyclic urea containingmoiety.

[0133] In yet another embodiment, the compound is defined according toformula 3 above except G₄ is phenylsulfonylamino.

[0134] In yet another embodiment, the compound is defined according toformula 3 above except G₄ is phenyl.

[0135] In yet another embodiment, the compound is defined according toformula 3 above except G₆ and G₇ are halogens.

[0136] In yet another embodiment, the compound is defined according toformula 3 above except G₆ and G₇ are both fluorine.

[0137] In yet another embodiment, the compound is defined according toformula 3 above except G₆ and G₇ are the same.

[0138] Particular compounds according to the present invention includethe following:

[0139] Compound I: 2′ (S) 5-(2′-Benzenesulfonylamino-2′-tert-butoxycarbonyl-ethylcarbamoyl)-thiophene-2-carboxylic acid.

[0140] Compound II:2-Benzenesulfonylamino-3-{[5-(3-tert-butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicacid- tert-butyl ester.

[0141] Compound III:2-Benzenesulfonylamino-3-{[5-(3-amino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicacid, trifluoracetic acid salt.

[0142] Compound IV:2-Benzenesulfonylamino-3-{[5-(3-guanidino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicacid, trifluoracetic acid salt.

[0143] Compound V:5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carboxylicacid.

[0144] Compound VI:3-{[5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicacid tert-butyl ester.

[0145] Compound VII:3-{[5-(3-Amino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicacid trifluoroacetic acid salt.

[0146] Compound VIII:3-{[5-(3-guanidino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicacid.

[0147] Compound IX: (2S)2-Benzenesulfonylamino-3-{[5-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-tiophen-2-carbonyl]-aminopropionic acid tert-butyl ester.

[0148] Compound X: (2S)2-Benzenesulfonylamino-3-{[5-(2-amino-ethylcarbamoyl)-tiophen-2-carbonyl]-aminopropionic acid trifluoroacetic acid salt.

[0149] Compound XI: (2S)2-Benzenesulfonylamino-3-{[5-(2-guanidinyl-ethylcarbamoyl)-thiophen-2-carbonyl]-aminopropionic acid hydrochloride salt.

[0150] Compound XII: (2s)2-Benzenesulfonylamino-3-(5-[2-(3-benzyl-ureido)-ethylcarbamoyl]-thiophen-2-carbonyl-amino)propionic acid.

[0151] Compound XIII: Dimethyl-2,5-thiophenedicarboxylic diester.

[0152] Compound XIV: 5-hydrazinocarbonyl-thiophene-2-carboxylic acidmethyl ester.

[0153] Compound XV:5-(N′-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carboxylic acidmethyl ester.

[0154] Compound XVI:5-(N-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carboxylic acid.

[0155] Compound XVII:2S-Benzenesulfonylamino-3-{[5-(N-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carbonyl]-amino{-propionicacid tert-butyl ester.

[0156] Compound XVIII:2S-Benzenesulfonylamino-3-[(5-hydrazinocarbonyl-thiophene-2-carbonyl)-amino]-3-propionicacid trifluoroacetate.

[0157] Compound XIX:2S-Benzenesulfonylamino-3-[(5-guanidino-aminocarbonyl-thiophene-2-carbonyl)-amino]-3-propionicacid trifluoroacetate.

[0158] Compound XX:(S)-3-((5-(2-Amino-ethylcarbamoyl)-furan-2-carbonyl)-amino)-2-benzenesulfonylamino-propionicacid trifluoroacetate.

[0159] Compound XXI:(s)-2-Benzenesulfonylamino-((5-(2-guanidino-ethylcarbamoyl)-furan-2-carbonyl)-amino)-propionicacid hydrochloride.

[0160] Compound XXIII: Thiophene-2,5-dicarboxylic acid monomethyl ester.

[0161] Compound XXIV: N,N′-Bis-(Boc)-N″-(2-Amino-ethyl)-guanidine.

[0162] Compound XXV:3-tert-Butoxycarbonylamino-2-(pyrimidin-2-ylamino)-propionic acid methylester.

[0163] Compound XXVI: (3-Amino-2-(pyrimidin-2-ylamino)-propionic acidmethyl ester bis hydrochloride salt.

[0164] Compound XXVII:5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylicacid methyl ester.

[0165] Compound XXXIX:3-{[5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid methyl ester.

[0166] Compound XXX:3-{[5-(2-guanidino-ethylcarbamoyl)-thiophene-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid bis trifluoroacetic acid salt.

[0167] Compound XXXI: [2-(1-Oxy-pyridin-2-ylamino)-ethyl)]-carbamic acidtert-butyl.

[0168] Compound XXXII: [2-(Pyridin-2-ylamino)-ethyl]-carbamic acidtert-butyl ester.

[0169] Compound XXXIII:5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic acidmethyl ester.

[0170] Compound XXXIV:3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid methyl ester.

[0171] Compound XXXV:3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid acetic acid salt.

[0172] Compound XXXVI:2-Benzenesulfonylamino-3-({5-[(1H-benzoimidazol-2-ylmethyl)-carbamoyl]-thiophene-2-carbonyl-amino)-propionicacid.

[0173] Compound XXXVII:3-({5-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-2-benzenesulfonylamino-propionicacid tert-butyl ester.

[0174] Compound XXXVIII:3-({5-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-2-benzenesulfonylamino-propionicacid trifluoroacetic acid salt.

[0175] Compound XXXIX: [2-(Pyrimidin-2-ylamino)-ethyl]-carbamicacid-tert-butyl ester.

[0176] Compound XL: N,1-Pyrimidin-2-yl-ethane-1,2-diaminetrifluoroacetic acid salt.

[0177] Compound XLI:2-Benzenesulfonylamino-3-({5-[2-(pyrimidin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl})-amino)-propionicacid tert-butyl ester.

[0178] Compound XLII:2-Benzenesulfonylamino-3-({5-[2-(pyrimidin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-propionicacid trifluoroacetic acid salt.

[0179] Compound XLIII:2-Benzenesulfonylamino-3-({5-[2-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-propionicacid, hydrochloride salt.

[0180] The term “alkyl” as used herein represents a straight orbranched, saturated or unsaturated chain having a specified total numberof carbon atoms (i.e. C₂ alkyl has two carbonatoms in the chain).

[0181] The term “phenyl” or “benzene” represent a six membered aromaticcarbon containing ring whether or not the ring is a substituent group orotherwise.

[0182] The term “amino” includes primary amines i.e. NH₂, secondaryamines i.e. NHR, or tertiary amines i.e. N(R)₂ wherein R is C₁₋₄ alkyl.Also encompassed by the term are quaternary amines such as NH₃ ⁺.

[0183] The term “guanidino” refers to the following structure:

[0184] The term “guanidino containing moiety” refers to a moiety thathas one carbon bound to three nitrogen.

[0185] The term “cyclic guanidino” refers to the following structure:

[0186] wherein Q is an alkyl.

[0187] The term “urea” refers generally to the following structure:

[0188] The term “urea containing moiety” refers to a moiety thatcontains a carbon bound to two nitrogen atoms and an oxygen atom.

[0189] The term “cyclic urea” refers to the following structure:

[0190] wherein Q is an alkyl.

[0191] The term “aryl” as defined herein refers to an aromatic ringhaving specified number of carbons (i.e. C₂ has two carbons) that mayoptionally be substituted with one or more heteroatoms selected from thegroup comprising O, N, or S.

[0192] The term “arylamino” refers to an aryl group, wherein the arylgroup is covalently bonded to an adjacent element through a nitrogenatom.

[0193] The term “sulfonyl” refers to a compound with the followingstructure:

[0194] The above terms also includes salts, esters, and salts of estersof the above corresponding structures unless designated otherwise.

[0195] The term “arylsulfonyl” refers to an aryl group, wherein the arylgroup is covalently bonded to an adjacent element through a sulfonyl(e.g. —SO₂—).

[0196] The term “phenylsulfonyl”, refers to a phenyl ring, wherein thephenyl ring is covalently bonded to an adjacent element through asulfonyl (e.g. —SO₂—)

[0197] The term “pyrimidinyl”, represents a six membered aryl thatcontains two nitrogen atoms separated by carbon.

[0198] The present invention also includes methods of making compoundsof formula 1 or any of the other formulas disclosed herein. Compounds ofthe present invention can be synthesized using conventional preparativesteps and recovery methods known to those skilled in the art of organicchemistry. A synthetic route according to-one embodiment of theinvention is illustrated in Scheme A and described as follows.

[0199] Referring to Scheme A, synthesis of compound A-8 is undertaken byreaction of compound A-1, which is dissolved in a solution containing aspecified amount of anhydrous dimethyl formamide (DMF) ando-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(HATU), with compound A-2 to yield compound A-3. Theresulting substituted 2,5-thiophene dicarboxylic acid is then coupledwith compound A-4 using HATU in the presence of anhydrous DMF to givecompound A-5. This product is then deprotected using a solution ofdichloromethane and trifluoroacetic acid (TFA) to yield compound A-6.The resulting TFA salt is then added to a reaction mixture composed ofdistilled water, DMF, diisopropylethylamine (DIPEA) and1H-pyrazole-1-carboxamidine hydrochloride (PCA) to give compound A-7.The resulting guanidino compound A-7 is reacted with benzyl isocyanateto give compound A-8.

[0200] Another synthetic route, according to one embodiment of thepresent invention, is illustrated in Scheme B and described as follows.

[0201] Referring to Scheme B, synthesis of compound B-7 is undertaken bycoupling compound B-1 with compound B-2 in anhydrous DMF using HATU. Theresulting product B-3 is then reacted with compound B-4 in anhydrous DMFusing HATU. The resulting disubstituted 2,5-thiophene dicarboxylic acidcompound B-5 is then deprotected using a solution of dichloromethane andTFA to yield compound B-6. The resulting TFA salt is then added to areaction mixture composed of distilled water, DMF, DIPEA and PCA to givethe guanidino compound B-7.

[0202] Another synthetic route according to one embodiment of thepresent invention is illustrated in Scheme C and described as follows.

[0203] Now referring to Scheme C, sodium hydride and iodomethane aresequentially added to a solution of compound C-1 in anhydrous DMF toyield compound C-2. The resulting dimethyl-2,5-thiophene diester is thenreacted with hydrazine in the presence of anhydrous dioxane to producecompound C-3. The resulting hydrazinocarbonyl group is then protectedusing Di tert-butyl dicarbonate in the presence of DIPEA to yieldcompound C-4. The methyl ester group is then hydrolyzed with an aqueousLiOH solution to yield compound C-5. The resulting monocarboxylic acidis then added to a reaction mixture containing compound C-6,N-methylmorpholine (NMM) and HATU to produce compound C-7. The resultingphenylsulfonylamino thiophene is then deprotected using dichloromethanein TFA to yield compound C-8. The resulting compound is finally reactedwith PCA compound to produce compound C-9.

[0204] Another synthetic route according to one embodiment of thepresent invention is illustrated in Scheme D and described as follows.

[0205] Benzotriazole-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate (Bop reagent) is added to compound D1. Afterstirring for 20 min., a solution of compound D2 and D3 are sequentiallyadded to yield compound D4. The resulting disubstituted thiophene isreacted with TFA in anhydrous dichloromethane to give compound D5. Theresulting TFA salt is then reacted with CPA and DIPEA to producecompound D6. To a mixture of the resulting guanidinyl compound is addeda portion of benzyl isocyanate to yield compound D7.

[0206] Another synthetic route according to one embodiment of thepresent invention is illustrated in Scheme E and described as follows.

[0207] Referring to Scheme E, synthesis of compound E7 is undertaken bycoupling compound E1 with compound E2 using HOBT and EDC. The resultingproduct E3 is then hydrolyzed with LiOH in THF to give themonocarboxylic acid compound E4. This product is then coupled withcompound E5 in the presence of HOBT and EDC to produce compound E6. Theresulting disubstituted 2,5-thiophene is then hydrolyzed with LiOH andconverted to the TFA salt to yield compound E7.

[0208] It will be appreciated by those skilled in the art that thecompounds of formulas 1, 2 and 3 depending on the substituents, maycontain one or more chiral centers and thus exist in the form of manydifferent isomers, optical isomers (i.e. enantiomers) and mixturesthereof including racemic mixtures. All such isomers, enantiomers andmixtures thereof including racemic mixtures are included within thescope of the invention.

[0209] It will particularly be appreciated by a person of ordinary skillin the art that the above disclosed schemes A, B, and C cover boththiophene compounds, where X is S, and furan compounds, where X is O.

[0210] One embodiment of the present invention comprises a method forinhibiting an integrin using a compound of formula 1 or any compound orformula disclosed herein.

[0211] Another embodiment of the present invention comprises a methodfor inhibiting an α_(v) integrin using a compound of formula 1 or anycompound or formula disclosed herein.

[0212] Another embodiment of the present invention comprises a methodfor inhibiting α_(v)β₃ using a compound of formula 1 or any compound orformula disclosed herein.

[0213] In yet another embodiment of the present invention comprises amethod for inhibiting α_(v)β₅ using a compound of formula 1 or anycompound or formula disclosed herein.

[0214] Another embodiment of the present invention comprises a methodfor inhibiting angiogenesis using a compound of formula 1 or anycompound or formula disclosed herein.

[0215] Another embodiment of the present invention comprises a methodfor preventing a cell from binding to osteopontin using a compound offormula 1 or any compound or formula disclosed herein.

[0216] Another embodiment of the present invention comprises a methodfor preventing a cell from binding to fibronectin using a compound offormula 1 or any compound or formula disclosed herein.

[0217] Another embodiment of the present invention comprises a methodfor treating a tumor using a compound of formula 1 or any compound orformula disclosed herein. In another aspect of this invention, the tumoris a solid tumor.

[0218] Another embodiment of the present invention comprises a methodfor treating metastasis using a compound of formula 1 or any compound orformula disclosed herein.

[0219] Another embodiment of the present invention comprises a methodfor treating cancer using a compound of formula 1 or any compound orformula disclosed herein.

[0220] Another embodiment of the present invention comprises a methodfor treating foot and mouth disease using a compound of formula 1 or anycompound or formula disclosed herein.

[0221] Another embodiment of the present invention comprises a methodfor treating osteoporosis using a compound of formula 1 or any compoundor formula disclosed herein.

[0222] Another embodiment of the present invention comprises a methodfor treating restenosis using a compound of formula 1 or any compound orformula disclosed herein.

[0223] Another embodiment of the present invention comprises a methodfor treating ocular diseases using a compound of formula 1 or anycompound or formula disclosed herein.

[0224] Another embodiment of the present invention comprises a methodfor treating heart diseases using a compound of formula 1 or anycompound or formula disclosed herein.

[0225] Another embodiment of the present invention comprises a methodfor treating arthritis using a compound of formula 1 or any compound orformula disclosed herein.

[0226] Another embodiment of the present invention comprises a methodfor treating diseases in which abnormal neovascularization occurs usinga compound of formula 1 or any compound or formula disclosed herein.

[0227] Another aspect of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one other anticancer agent or antiangiogenic agent.

[0228] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one other chemotherapeutic agent.

[0229] One embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one other anticancer agent selected from the group consistingof alkylating agents, antitumor antibiotics, antimetabolites, biologicalagents, hormonal agents, nitrogen mustard derivatives and plantalkaloids.

[0230] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one alkylating agent selected from the group consisting ofbusulfan, carboplatin, carmustine, semustine, sibiromycin, cisplatin,cyclophosphamide, decarbazine, ifosfamide, lomustine or strotozocin.

[0231] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one antitumor antibiotic selected from the group consisting ofbleomycin, dactinomycin, daunorubicin, doxorubicin, idonubicin,mitomycin-C and plicamycin.

[0232] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one antimetabolite selected from the group consisting ofcytarabines, prednisones, floxuridine, 5-fluorouracil, fludarabine,hydroxyureas, mercaptopurines, methotrexate and thioguanine.

[0233] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one biological agent selected from the group consisting ofaldeleukin, interferonα-2a, interferonα-2b, interferonα-n3,interferon8-1B and interleukin-2.

[0234] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one hormonal agent selected from the group consisting ofaminoglutethimide, anastrozole, flutamide, goserelin, megestrol,mitotane and tamoxifen.

[0235] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one nitrogen mustard derivative selected from the groupconsisting of clorambucil, estramustine, michlorethamine, melphalan andthiotepa.

[0236] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one plant alkaloide selected from the group consisting ofdocetaxel, etoposide, irinotecan, paclitaxel, teniposide, topotecan,vinblastine, vincristine and vinorelbine.

[0237] Another embodiment of the present invention comprises using acompound of formula 1 or any compound or formula disclosed herein withat least one agent selected from the group consisting of troxacitabine,altretamine, amifostine, asparaginase-escherichia coli, BCG live,cladribine, gemcitabine, leucovorin, levamisole, mitoxantrone,pegaspargase, pentostatin and procarbazine.

[0238] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined abovetogether with a pharmaceutically acceptable carrier therefor comprise afurther aspect of the invention.

[0239] One embodiment of the present invention also providescompositions which comprise a pharmaceutically acceptable carrier oradjuvant and an effective amount of a compound of formula 1, 2 or 3 toinhibit angiogenesis and/or tumor growth in a mammal. The proportion ofeach carrier, diluent or adjuvant is determined by the solubility andchemical nature of the compound and the route of administrationaccording to standard pharmaceutical practice.

[0240] The individual components of such combinations may beadministered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

[0241] When the compound of formula 1 or any compound or formuladisclosed herein is used in combination with a second therapeutic agent,the dose of each compound may be either the same as or differ from thatwhen the compound is used alone. Appropriate doses will be readilyappreciated by those skilled in the art.

[0242] Therapeutic and prophylactic methods of this embodiment of theinvention comprise the step of treating patients in a pharmaceuticallyacceptable manner with those compounds or compositions. Suchcompositions may be in the form of tablets, capsules, caplets, powders,transdermal patches, granules, lozenges, suppositories, reconstitutablepowders, or liquid preparations, such as oral or sterile parenteralsolutions or suspensions.

[0243] In order to obtain consistency of administration, it is preferredthat a composition of the invention is in the form of a unit dose. Theunit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients. For example, bindingagents, such as acacia, gelatin, sorbitol, or polyvinylpyrrolidone;fillers, such as lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tableting lubricants such as magnesium stearate;disintegrants, such as starch, polyvinylpyrrolidone, sodium starchglycollate or microcrystalline cellulose; or pharmaceutically acceptablewetting agents such as sodium lauryl sulphate.

[0244] The compounds may be injected parenterally; this beingintramuscularly, intravenously, or subcutaneously. For parenteraladministration, the compound may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic. The amount of active ingredientadministered parenterally will be approximately 0.01 to 250 mg/kg/day,preferably about 1 to 10 mg/kg/day, more preferably about 0.5 to 30mg/kg/day, and more most preferably about 1-20 mg/kg/day.

[0245] The compounds may be administered orally in the form of tablets,capsules, or granules containing suitable excipients such as starch,lactose, white sugar and the like. The compounds may be administeredorally in the form of solutions which may contain coloring and/orflavoring agents. The compounds may also be administered sublingually inthe form of tracheas or lozenges in which each active ingredient ismixed with sugar or corn syrups, flavoring agents and dyes, and thendehydrated sufficiently to make the mixture suitable for pressing intosolid form. The amount of active ingredient administered orally willdepend on bioavailability cf the specific compound.

[0246] The solid oral compositions may be prepared by conventionalmethods of blending, filling, tableting, or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art. The tablets may be coated accordingto methods well known in normal pharmaceutical practice, in particularwith an enteric coating.

[0247] Oral liquid preparations may be in the form of emulsions, syrups,or elixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations mayor may not contain conventional additives. For example suspendingagents, such as sorbitol, syrup, methyl cellulose, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, orhydrogenated edible fats; emulsifying agents, such as sorbitanmonooleate or acaci; non-aqueous vehicles (which may include edibleoils), such as almond oil, fractionated coconut oil, oily estersselected from the group consisting of glycerine, propylene glycol,ethylene glycol, and ethyl alcohol; preservatives, for instance methylpara-hydroxybenzoate, ethyl para-hydroxybenzoate, n-propylparahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and,if desired, conventional flavoring or coloring agents.

[0248] For parenteral administration, fluid unit dosage forms may beprepared by utilizing the peptide and a sterile vehicle, and, dependingon the concentration employed, may be either suspended or dissolved inthe vehicle. Once in solution, the compound may be injected and filtersterilized before filling a suitable vial or ampoule and subsequentlysealing the carrier or storage package. Adjuvants, such as a localanesthetic, a preservative or a buffering agent, may be dissolved in thevehicle prior to use. Stability of the pharmaceutical composition may beenhanced by freezing the composition after filling the vial and removingthe water under vacuum, (e.g., freeze drying the composition).Parenteral suspensions may be prepared in substantially the same manner,except that the compound should be suspended in the vehicle rather thanbeing dissolved, and, further, sterilization is not achievable byfiltration. The compound may be sterilized, however, by exposing it toethylene oxide before suspending it in the sterile vehicle. A surfactantor wetting solution may be advantageously included in the composition tofacilitate uniform distribution of the compound.

[0249] The pharmaceutical composition of this invention comprise acompound of formula 1, 2 or 3 and a pharmaceutically acceptable carrier,diluent or adjuvant. Typically, they contain from about 0.1% to about99% by weight of active compound, and preferably from about 10% to about60% by weight depending on which method of administration is employed.

[0250] A pharmaceutically effective amount of compounds of the inventioncan be determined according to one or more of the assays described indetail in the examples. Under these particular conditions, a compoundhaving such activity will exhibit an IC₅₀ of approximately 50 μg/ml orless, preferably 25 μg/ml or less, more preferably 10 μg/ml or less, andmost preferably less than 1 μg/ml

[0251] Physicians will determine the dosage of the present therapeuticagents which will be most suitable. Dosages may vary with the mode ofadministration and the particular compound chosen. In addition, thedosage may vary with the particular patient under treatment. The dosageof the compound used in the treatment will vary, depending on manyfactors including the weight of the patient, the relative efficacy ofthe compound and the judgment of the treating physician. Such therapymay extend for several weeks or months, in an intermittent oruninterrupted manner.

[0252] To further assist in understanding the present invention, thefollowing non-limiting examples are provided.

Example 1 Synthesis of the Compounds

[0253] Compound I: (2′S) 5-(2′-Benzenesulfonylamino-2′-tert-butoxycarbonyl-ethylcarbamoyl)-thiophene-2-carboxylic Acid.

[0254] Referring now to Scheme F herein, 2,5 thiophene dicarboxilic acid(200 mg, 1.16 mmol) was dissolved in 2 ml of anhydrous DMF and to thissolution was added (2S) 3-Amino-2-benzenesulfonylamino-propionic acid-tert-butyl ester (243 mg, 0.58 mmol), HATU (244 mg, 0.80 mmol) and2,4,6-collidine (0.5 ml, 4.1 mmol). This reaction mixture was then leftstirring at room temperature for two days. The solvent was evaporatedunder reduced pressure, the resulting residue was chromatographed onsilica gel using first 10% acetone in dichloromethane, then 20% acetonein dichloromethane to clear out the impurities and the desired productwas flushed out using a 50-50 acetone dichloromethane mixture.Evaporation of the desired fraction gave 200 mg of a white powder(Compound I). ¹H NMR (400 MHz, DMSO-d6) 1.12 (s, 9H), 3.3 (m, 1H), 3.4(m, 1H), 4.0 (q, 1H), 7.55 (m, 3H), 7.6 (d, 1H), 7.7 (d, 1H), 7.75 (d,2H), 8.4 (d, 1H), 8.8 (t, 1H).

[0255] Compound II:2-Benzenesulfonylamino-3-{[5-(3-tert-butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicAcid-tert-butyl Ester.

[0256] With continued reference to Scheme F, Compound I:(2′S)5-(2′-Benzenesulfonylamino-2′-tert-butoxycarbonyl-ethylcarbamoyl)-thiophene-2-carboxylicacid (200 mg, 0.47 mmol) was dissolved in 2 ml of anhydrous DMF and tothis solution was added 1-N-Boc-1,3-diaminopropane (110 mg, 0.71 mmol),HATU (231 mg, 0.61 mmol) and 2,4,6-collidine (0.5 ml, 4.1 mmol). Thisreaction mixture was then left stirring at room temperature for 24 hrs.A large amount of ethyl acetate was added to the reaction mixture whichwas then washed successively with a 10% citric acid aqueous solution, asodium bicarbonate solution and then brine. After separation the organicphase was dried over anhydrous MgSO₄ then filtrated on a pad of silicagel and the solvents were removed under reduced pressure to give 180 mgof a white powder (Compound II). ¹H NMR (400 MHz, CDCl3) 1.3 (s, 9H),1.5 (s, 9H), 1.7 (m, 2H), 3.3 (m, 2H) 3.5 (m, 2H), 3.55 (m, 1H), 3.9 (m,2H), 4.85 (m, 1H), 5.65 (m, 1H), 6.7 (m, 1H), 7.45 (m, 1H), 7.55 (m,4H), 7.6 (m, 1H), 7.9 (d, 2H).

[0257] Compound III:2-Benzenesulfonylamino-3-{[5-(3-amino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicAcid, Trifluoracetic Acid Salt.

[0258] With continued reference to Scheme F, Compound II: 2-Benzene-sulfonylamino-3-{[5-(3-tert-butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicacid-tert-butyl ester (180 mg, 0.95 mmol) was dissolved in 10 mldichloromethane and 4.5 ml of anhydrous TFA. This reaction mixture wasthen left stirring over night at room temperature. The solvents werethen removed under reduced pressure and the residue was dissolved in asmall amount of methanol, then ether was added and the desired productprecipitated out of the solution, the liquid was discarded and theresidue was dried under vacuum to give a white powder (160 mg, 95%)(Compound III). ¹H NMR (400 MHz, DMSO) 1.8 (m, 2H), 2.8 (m, 2H), 3.3 (m,3H), 3.5 (m, 1H), 3.9 (m, 1H), 7.45 (m, 2H), 7.55 (m, 1H), 7.6 (d, 1H),7.7 (d, 1H), 7.75 (bs, 4H), 7.75 (d, 2H), 8.6 (m, 1H), 8.75 (m, 1H)

[0259] Compound IV:2-Benzenesulfonylamino-3-{[5-(3-guanidino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicAcid, Trifluoracetic Acid Salt.

[0260] With continued reference to Scheme F. Compound III:2-Benzenesulfonylamino-3-{[5-(3-amino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionicacid, trifluoracetic acid salt (70 mg, 0.123 mmol) was dissolved in 2.0ml distilled water containing 2.5 ml DMF with PCA (36 mg, 0.246 mmol)and DIPEA (158 mg, 1.23 mmol). This reaction mixture was heated untildissolution of the reagents then left to react over night at roomtemperature. The reaction mixture was concentrated under reducedpressure then chromatographed on silica gel using ethanol then 10%ammonium hydroxide in ethanol to elute starting materials then 20%ammonium hydroxide in ethanol to elute the desired product. Evaporationof the desired fraction gave 10 mg of a white powder (Compound IV). ¹HNMR (400 MHz, DMSO) 1.65 (m, 2H), 3.1 (m, 2H), 3.2 (m, 2H), 3.4 (2H),3.5 (m, 1H), 7-7.4 (bm, 5H), 7.5 (m, 4H), 7.65 (d, 1H), 7.8 (d, 2H), 8.2(m, 1H), 8.55 (m, 1H), 8.75 (m, 1H).

[0261] Compound V:5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carboxylicAcid.

[0262] Referring now to Scheme G herein, 2,5-thiophene dicarboxylic acid(1 g, 5.8 mmol) was reacted with N-Boc-1,3-diaminopropane (0.9 g, 5.8mmol) in 20 ml of anhydrous DMF using HATU (2.2 g, 5.8 mmol) with2,4,6-collidine (2.5 ml, 5.8 mmol), chromatographied on silica gel usingethyl acetate: methanol (9:1) to give 350 mg (18% yield) of the desiredproduct (Compound V) contaminated with the product of bis addition. ¹HNMR (400 MHz, DMSO-d6) 1.3 (s, 9H), 1.6 (m, 2H), 2.95 (m, 2H), 3.2 (m,2H), 7.7 (m, 2H), 8.6 (t, 1H).

[0263] Compound VI:3-{[5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicAcid Tert-butyl Ester.

[0264] With continued reference to Scheme G,5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carboxylicacid (200 mg, 0.704 mmol) was reacted with 3-Amino-3-phenyl-propionicacid tert-butyl ester (187 mg, 0.845 mmol) in 4.0 ml of anhydrous DMFusing HATU (321 mg, 0.845 mmol) with 2,4,6-collidine (0.25 ml, 2.112mmol), chromatographied on silica gel using ethyl acetate: hexane (8:2)to give 200 mg (58% yield) of the desired product as a clear semi-solidoil. ¹H NMR (400 Mhz, CDCl₃) 1.3 (s, 9H), 1.45 (s, 9H), 1.7 (m, 2H), 2.9(ddd, 2H), 3.25 (m, 2H), 3.5 (q, 2H), 4.85 (bs, 1H), 5.55 (m, 1H), 7.23(m, 1H), 7.33 (m, 4H), 7.4-7.6 (m, 4H).

[0265] Compound VII:3-{[5-(3-Amino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicAcid Trifluoroacetic Acid Salt.

[0266] With continued reference to Scheme G, preparation of compound VIIwas carried out using the procedure described for compound III. CompoundVI:3-{[5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicacid tert-butyl ester (200 mg, 0.704 mmol) was dissolved in 4.0 ml ofanhydrous dichloromethane and 4.0 ml of anhydrous TFA. This reactionmixture was left stirring over night at room temperature. The solventswere evaporated under reduced pressure and the resulting residue wasdissolved in anhydrous methanol (smallest amount possible). Diethylether was then added to precipitate the desired product, the supernatantwas discarded and the solid washed with ether again then dried underreduced pressure to give 156 mg of the desired product as a white powder(Compound VII). ¹H NMR (400 Mhz, DMSO-d6) 1.75 (m, 2H), 2.9 (m, 4H), 3.3(m, 2H), 7.2-7.4 (m, 5H), 7.4 7.9 (bs, 3H), 7.65 (d, 1H), 7.8 (d, 1H),8.75 (t, 1H), 9.05 (d, 1H).

[0267] Compound VIII: 3-{[5(3-guanidino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicAcid.

[0268] With continued reference to Scheme G. Compound VII:3-{[5-(3-Amino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionicacid (50 mg, 0.102 mmol) was dissolved 1.0 ml in anhydrous DMF with PCA(30 mg, 0.204 mmol) and DIPEA (0.3 ml, 1 mmol). This reaction mixturewas heated at 60-70° C. for 4 hours. The reaction mixture wasconcentrated under reduced pressure then chromatographed on silica gelusing ethanol then 10% ammonium hydroxide in ethanol to elute startingmaterials then 40% ammonium hydroxide in ethanol to elute the desiredproduct. Evaporation of the desired fraction gave 21 mg (50% yield) of awhite powder. Compound VIII ¹H NMR (400 MHz, DMSO) 1.7 (m, 2H), 2.7 (m,1H), 3.1 (m, 2H), 3.25 (m, 2H), 5.25 (m, 1H), 7.2-7.4 (m, 5H), 7.6 (bs,4H), 7.7 (d, 1H), 7.75 (d, 1H), 8.8 (s, 1H), 8.9 (s, 1H), 9.65 (s, 1H)

[0269] Compound IX: (2S)2-Benzenesulfonylamino-3-{[5-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-thiophen-2-carbonyl]-aminoPropionic Acid Tert-butyl Ester.

[0270] Referring now to Scheme H, benzotriazole-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (Bop reagent) (514 mg,1.162 mmol) as added, in one portion, to a mixture of 2,5-thiophenedicarboxylic acid (100 mg, 0.581 mmol). The mixture was stirred for 20min. and a solution of the 3-tert-butylcarbonylaminoethylamine (93 mg,0.581 mmol) in 1 ml of the same solvent, was added one drop at a time.This mixture was stirred for 6 hours. A solution of2-benzenesulfonylamino-3-amino-propionic acid tert-butylesterhydrochloride (196 mg, 0.581 mmol) and dimethylaminopyridine (355 mg,2.905 mmol) in 1 ml of the same solvent was added dropwise. The mixturewas stirred overnight, concentrated (to eliminate the DMF), diluted inethyl acetate, washed with KHSO4 10%, NaHCO3 sat. , brine and dried(anhydrous MgSO₄). Flash chromatography usingdichloromethane:acetone(85:15) gave 157 mg of the pure desired product(Compound IX: 45% yield). ¹H NMR (400 MHz, CD3OD) 1.24 (s, 9H), 1.42 (s,9H), 3.25-3.28 (m, 2H), 3.42-3.45 (m, 2H), 3.46-3.52 (dd, 1H), 3.63-3.69(dd, 1H), 4.10-4.14 (dd, 1H), 7.47-7.51 (m, 2H), 7.53-7.57 (m, 3H),7.60-7.61 (m, 2H), 7.83-7.85 (m, 2H).

[0271] Compound X: (2S)2-Benzenesulfonylamino-3-[5-(2-amino-ethylcarbamoyl)-thiophen-2-carbonyl]-aminoPropionic Acid Trifluoroacetic Acid Salt.

[0272] With continued reference to Scheme H, TFA (1.5) ml was added to amixture of Compound IX: (2S)2-Benzenesulfonylamino-3-{[5-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-thiophen-2-carbonyl]-aminopropionic acid tert-butyl ester (151 mg, 0.253 mmol) in anhydrousdichloromethane (1.5 ml). The mixture was stirred 1 hour (and wasfollowed on TLC) then concentrated. The crude oil residue was trituratedin ether and filtrated to give the deprotected amino acid (white solid)as a TFA salt which was used in the next experiment without furtherpurification (Compound X). ¹H NMR (400 MHz, CD3OD) 3.14-3.18 (m, 2H),3.45-3.51 (m, 1H), 3.63-3.67 (m, 2H), 3.71-3.76 (dd, 1H), 4.17-4.21 (dd,1H), 7.43-7.54 (m, 3H), 7.58 (d, 1H), 7.64 (d, 1H), 7.83-7.85 (dd, 1H).

[0273] Compound XI: (2S)2-Benzenesulfonylamino-3-[5-(2-guanidinyl-ethylcarbamoyl)-thiophen-2-carbonyl]-aminoPropionic Acid Hydrochloride Salt.

[0274] With continued reference to Scheme H, Compound X: (2S)2-Benzenesulfonylamino-3-[5-(2-amino-ethylcarbamoyl)-thiophen-2-carbonyl]-aminopropionic acid TFA salt was dissolved in 1.25 ml of water and 1.25 ml ofDMF. DIPEA (132 ul, 0.759 mmol) and PCA (56 mg, 0.380 mmol) were addedsuccessively. The mixture was stirred at 60° C. for 6 hours, cooled downto room temperature (room temperature) and concentrated. Flashchromatography ethanol: ammonium hydroxide:water (8:1:1) gave theguanidinyl compound which was lyophilized in a HCl 0.05 N in water togive 95 mg of the desired compound as a hydrochloride salt. ¹H NMR (400MHz, CD3OD) 3.43-3.46 (m, 2H), 3.47-3.51 (m, 1H), 3.54-3.55 (m, 2H),3.71-3.75 (dd, 1H), 4.18-4.20 (dd, 1H), 7.43-7.51 (m, 3H), 7.57 (bm,1H), 7.64 (bm, 1H), 7.83 (m, 2H).

[0275] Compound XII: (2S)2-Benzenesulfonylamino-3-(5-[2-(3-benzyl-ureido)-ethylcarbamoyl]-thiophen-2-carbonyl-amino)Propionic Acid.

[0276] With continued reference to Scheme H, to a mixture of Compound X:(2S)2-Benzenesulfonylamino-3-[5-(2-amino-ethylcarbamoyl)-thiophen-2-carbonyl]-amino)propionic acid TFA salt (23 mg, 0.042 mmol) in acetonitrile (0.25 ml)and anhydrous DMF (0.25 ml) was added triethylamine (11.7 uL, 0.084mmol) and benzyl isocyanate (5.3 uL, 0.042 mmol). The mixture wasstirred for 20 min. An additional portion of benzyl isocyanate (2.5 uL)was added. After 1 hour of stirring, the mixture was diluted with ethylacetate, washed with HCl 0.1 N and dried (Na₂SO₄). Filtration of thecrude through silica mega bound elute system methanol dichloromethane(4:6) and evaporation of the desired fractions gave a white powder(Compound XII). ¹H NMR (300 MHz, D2O) 3.15-3.25 (m, 3H), 3.30-3.33 (m,2H), 3.49-3.55 (dd, J=14.5 and 3.5 Hz, 1H), 3.75-3.80 (dd, J=10.5 and4.0 Hz, 1H), 4.09 (s, 2H), 7.04-7.08 (m, 5H), 7.12-7.13 (m, 4H), 7.29(d, J=4.0 Hz, 1H), 7.54-7.58 (m, 2H).

[0277] Compound XIII: Dimethyl-2,5-thiophenedicarboxylic Diester.

[0278] Now referring to Scheme I, sodium hydride, 60% in oil, (1.9 g,0.046 mol) was added to a stirring solution of 2,5-thiophenedicarboxylicacid (4.0 g, 0.023 mol) in anhydrous DMF (40 ml). This reaction mixturewas left stirring at room temperature for an additional 10 min. Theniodomethane (6.0 ml) was added and the resulting suspension was stirred24 hrs at room temperature. The solvent was evaporated under reducedpressure and the residue was extracted with a mixture of ethylacetate:distilled water and the organic layer was separated and the solvent wasevaporated under reduced pressure, the residue was triturated withhexane (diethyl ether can also be used), then dried under vacuum leaving(4 g, 86%) of a pale yellow powder Compound XIII: ¹H NMR (300 MHz,CDCl₃) 3 3.92 (s, 6H), 7.73 (s, 2H).

[0279] Compound XIV: 5-hydrazinocarbonyl-thiophene-2-carboxylic AcidMethyl Ester.

[0280] With continued reference to Scheme I, Compound XIII:Dimethyl-2,5-thiophenedicarboxylic diester (600 mg, 3 mmol) wasdissolved in 20 ml of anhydrous dioxane and hydrazine (192 mg, 6 mmol).This solution was stirred at room temperature for 7 days. During thisperiod of time a precipitate formed at the bottom of the flask. Thisprecipitate was filtrated then dried under reduced pressure to give awhite powder Compound XIV (200 mg, 33%). ¹H NMR (300 MHz, DMSO) 3.8 (s,3H), 7.7 (d, 1H), 7.8 (d, 1H), 9.9 (s, 1H), 10.1 (s, 1H).

[0281] Compound XV:5-(N′-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carboxylic AcidMethyl Ester.

[0282] With continued reference to Scheme I, di tert-butyl dicarbonate(188 mg, 0.861 mmol) and DIPEA (170 μl, 0.976 mmol) were sequentiallyadded to a stirring mixture of Compound5-Hydrazinocarbonyl-thiophene-2-carboxylic acid methyl ester (115 mg,0.575 mmol) in anhydrous DMF (2.0 ml) at 0° C. The resulting mixture wasallowed to stir at room temperature overnight. The solvent was removedunder vacuum and the resulting residue subjected to a silica gelchromatography using Hexane: EtOAc (1:1) to give the desired product asa white solid (107.7 mg, 62.4%) ¹H NMR in DMSO-d₆ 1.42 (s, 9H), 3.84 (s,3H), 7.72-7.88 (m, 2H), 9.06 (bs, 1H), 10.5 (bs, 1H);

[0283] Compound XVI:5-(N-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carboxylic Acid.

[0284] With continued reference to Scheme I, a 2 mL aqueous LIOHsolution (35.7 mg, 85 mmol, lithium hydroxide monohydrate in 2 mL H₂O)was added to a stirring solution of Compound XV: 5-(N′tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carboxylic acidmethyl ester (85 mg, 0.28 mmol) in THF (4 ml) at room temperature. Themixture was stirred at room temperature overnight. The organic solventwas evaporated and the mixture acidified with HCl (1M solution in ether)to pH=5. The desired acid (Compound XCVI) was collected by filtrationand used in the next step without further purification (70 mg, 86%). ¹HNMR CD₃OD 1.42 (s, 9H), 7.86-7.79 (m, 2H), 9.06 (bs, 1H), 10.43 (bs,1H).

[0285] Compound XVII:2S-Benzenesulfonylamino-3-{[5-(N-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carbonyl]-amino}-propionicAcid Tert-butyl Ester.

[0286] With continued reference to Scheme I,3-amino-2S-benzenesulfonylamino-propionic acid tert-butyl esterhydrochloride (64.7 mg, 0.192 mmol), NMM (57.7 μl, 0.525 mmol) and HATU(76.4 mg, 2.01 mmol) were sequentially added to a stirring mixture of5-(N′-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carboxylic acid(50 mg, 0.175 mmol) in anhydrous DMF (5.2 ml) at room temperature. Theresulting mixture was allowed to stir at room temperature for 2 hrs. Thesolvent was removed under vacuum and the resulting residue subjected toa silica gel chromatography EtOAc: Hexane (1.5:0.5) to give the desiredproduct (Compound XVII) as a white solid (90 mg, 91%): ¹H NMR in CDCl₃1.29 (s, 9H), 1.48 (s, 9H), 3.70-3.85 (m, 3H), 4.05 (m, 1H), 6.38 (bs,1H), 7.18 (bs, 1H), 7.35-7.90 (m, 7H), 9.44 (bs, 1H);

[0287] Compound XVIII:2S-Benzenesulfonylamino-3-[(5-hydrazinocarbonyl-thiophene-2-carbonyl)-amino]-3-propionicAcid Trifluoroacetate.

[0288] With continued reference to Scheme I, TFA (0.6 ml) was added to astirred solution of Compound XVII:2S-Benzenesulfonylamino-3-{[5-(N′-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carbonyl]-amino-propionicacid tert-butyl ester (10 mg, 0.0176 mmol) in dichloromethane (0.6 ml)at room temperature. The resulting mixture was stirred at roomtemperature for 45 min. The solvent was removed under vacuum and theresulting residue was triturated from MeOH-Et2O to give the desiredproduct (compound XVIII) (6.8 mg, 74%) m.p. 185° C. (dec), ¹H NMR inDMSO-d₆ 3.45-3.55 (m, 1H), 4.0 (dd, 1H), 7.4-7.55 (m, 3H), 7.57 (d, 1H),7.64 (d, 1H), 7.70-7.78 (m, 2H), 8.24 (d, 1H), 8.62, (t, 1H), 10.06 (bs,1H); m/z 413 M⁺.

[0289] Compound XIX:2S-Benzenesulfonylamino-3-[(5-guanidino-aminocarbonyl-thiophene-2-carbonyl)-amino]-3-propionicAcid Trifluoroacetate.

[0290] With continued reference to Scheme I, TFA (1.2 ml) was added to astirred solution of Compound XVIII:2S-Benzenesulfonylamino-3-{[5-(N′-tert-Butoxycarbonyl-hydrazinocarbonyl)-thiophene-2-carbonyl]-amino{-propionicacid tert-butyl ester (30 mg, 0.053 mmol) in dichloromethane (1.2 ml) atroom temperature. The resulting mixture was stirred at room temperaturefor 45 min. The solvent was removed under vacuum and the resultingresidue was redissolved in DMF-H₂O (0.4 ml/0.4 ml). PCA (15.48 mg, 0.106mmol) and DIPEA (73.6 μl, 0.423 mmol) were added. The resulting mixturewas heated at 60° C. for 4 hours and then the solvent was evaporated toyield a solid residue. Chromatography of the crude EtOH H2O: NH₄OH(1.8:0.1:0.1) gave the desired product which was lyopholized to affordthe product as a white solid (13 mg, 54w. Part of the product was mixedwith dichloromethane (5 ml), a few drops of methyl alcohol and TFA. Themixture was turn clear and the solvent was evaporated to a white solidwhich was further triturated from MeOH-Et2O to afford purer product(Compound XIX); 205° C. (dec). ¹H NMR in CD3OD 3.73 (dd, 1H), 4.19 (dd,1H), 3.46 (dd, 1H), 7.40-7.55 (m, 3H), 7.59 (d, 1H), 7.73 (d, 1H),7.78-7.85 (m, 2H); m/z 455 M⁺.

[0291] Compound XX:(S)-3-((S-(2-Amino-ethylcarbamoyl)-furan-2-carbonyl)-amino)-2-benzenesulfonylamino-propionicAcid Trifluoroacetate.

[0292] Compound XX was made using 2,5-furan dicarboxylic acid as thestarting material. Otherwise, the same procedure was followed asillustrated in Scheme H for producing compound X. The resulting compoundwas obtained as a white powder: (HNMR, 400 MHz, CD₃OD) d: 7.85 (m, 2H),7.35-7.55 (m, 3H), 7.17 (d, 1H), 7.12 (d, 1H), 4.07 (dd, 1H), 3.64-3.80(m, 3H), 3.55 (dd, 1H), 3.19 (br, 2H).

[0293] Compound XXI:(s)-2-Benzenesulfonylamino-((5-(2-guanidino-ethylcarbamoyl)-furan-2-carbonyl)-amino)-propionicAcid Hydrochloride.

[0294] Compound XXI was made using 2,5 dicarboxilic acid as a startingmaterial. Otherwise the same procedure was followed as illustrated inScheme II for producing Compound XI. Compound XXI was obtained as awhite lyophilized powder: (HNMR, 400 MHz, CD₃OD) d: 7.83 (m, 2H),7.35-7.50 (m, 3H), 7.18 (d, 1H), 7.09 (d, 1H), 4.22 (dd, 1H), 3.78 (dd,1H), 3.60 (m, 2H), 3.47 (m, 3H).

[0295] Compound XXII: Dimethyl-2,5-thiophenedicarboxylic Diester.

[0296] Now referring to Scheme J, to a stirring solution of2,5-thiophenedicarboxylic acid (4.0 g, 0.023 mol) in anhydrous DMF (40ml), was added sodium hydride, 606 in oil, (1.9 g, 0.046 mol) and th-sreaction mixture was left stirring at room temperature -or an additional10 min. Then iodomethane (6.0 ml) was added and the resulting suspensionwas stirred 24h at room temperature. The solvent was evaporated underreduced pressure and the residue was extracted with a mixture ofethylacetate: distilled water and the organic layer was separated andthe solvent was evaporated under reduced pressure, the residue wastriturated with hexane (diethyl ether can also be used), then driedunder vacuum leaving (4 g, 86%) of a pale yellow powder (Compound XXII)¹H NMR (300 MHz, CDCl₃) 3.92 (s, 6H), 7.76 (s, 2H)

[0297] Compound XXIII: Thiophene-2,5-dicarboxylic Acid Monomethyl Ester.

[0298] With continued reference to Scheme J, to a suspension of CompoundXXII: dimethyl-2,5-thiophenedicarboxylic diester (4.13 g, 20.65 mmol) indry MeOH (150 mL) was added to a solution potassium hydroxide (1.272 g,22.72 mmol) in MeOH (10 mL). The mixture was then stirred at 60° C.overnight for. 18 hours. The solvent was then removed under vacuum andthe resulting residue was triturated with ethyl acetate and dried undervacuum. The resulting solid was then dissolved in water (20 mL) and theresulting solution was filtered and the filtrate was then acidified withHCl (1 N). The precipitate (Compound XXIII) was then collected byfiltration and dried under vacuum (2.50 g, 65w). ¹H NMR (300 MHz, DMSO)δ: 13.73 (br s , 1H), 7.79 (d, 1H), 7.72 (d, 1H), 3.85 (s, 3H).

[0299] Compound XXIV: N,N′-Bis-(Boc)-N″-(2-Amino-ethyl)-guanidine.

[0300] With continued reference to Scheme J, a solution of theN,N′-bis-(Boc)-1H-Pyrazole-1-carboxamidine (2 g, 6.45 mmol) in THF (50ml) was added dropwise to ethylene diamine (4 ml, 59.6 mmol) in THF (100ml). After 30 min of mixing at room temperature solvent was evaporatedthen toluene (100 ml) was added and evaporated in order to removeremaining traces of the ethylene diamine. The resulting product(Compound XXIV) was treated immediately according to scheme K since itdecomposes at room temperature. ¹H NMR (CDCl₃, 400 MHz) δ 1.40-1.61 (m,18H), 2.87-2.90 (t, 2H,), 3.47-3.50 (m, 2H), 6.31-6.34 (t, 0.61H),7.61-7.62 (d, 1H), 8.45-8.66 (broad s).

[0301] Compound XXV:3-tert-Butoxycarbonylamino-2-(pyrimidin-2-ylamino)-propionic Acid MethylEster.

[0302] With continued reference to Scheme J, methyl2-amino-3(N-t-butyoxycarbonylamino)propionate (240 mg, 1.10 mmol),2-bromopyrimidine (350 mg, 2.20 mmol) is obtained according to thedisclosure found in Egbertson et al., Synthetic Communications, vol. 23,pp. 703 et seq. (1993) incorporated herein fully by reference. Methyl2-amino-3-(N-E-butyoxy carbonyl amino) propionate was then mixed withand sodium carbonate (117 mg, 1.10 mmol) in DMF (1 mL). The resultingmixture was stirred at 100° C. for about 20 hours. The reaction mixturewas concentrated under vacuum and the residue was purified bychromatography eluting with 50% ethyl acetate in hexane. The resultingproduct Compound XXV was obtained as a foam (174 mg, 53%) ¹H NMR (400MHz, CDCl₃) δ:8.30 (d, 2H), 6.61 (t, 1H) 6.02 (br s, 1H), 4.94 (br s,1H), 4.76 (br d, 1H), 3.78 (s, 3H), 3.67 (br s, 2H), 1.43 (s, 9H).

[0303] Compound XXVI: (3-Amino-2-(pyrimidin-2-ylamino)-propionic AcidMethyl Ester Bis Hydrochloride Salt.

[0304] With continued reference to Scheme J, a solution of Compound XXV:3-tert-Butoxycarbonylamino-2-(pyrimidin-2-ylamino)-propionic acid methylester (227 mg, 0.77 mmol) in HCl/dioxane (4 N, 5 mL) was stirred at roomtemperature for 1 hour. The solution was then concentrated to drynessand the residue was dissolved in water (20 mL). This solution was thenwashed with dichloromethane (2×10 mL) and hexanes (10 mL). The solutionwas then filtered and lyophilized to a yellow solid (Compound XXVI: 185mg, 90%) ¹H NMR (400 MHz, DMSO) δ:8.70 (d, 2H), 8.20 (br s, 2H), 7.69(br d, 1H), 6.75 (t, 1H), 5.79 (br, 3H), 4.80 (br d, 1H), 3.78 (s, 3H),3.64 (br s, 2H), 3.2 (br s, 2H).

[0305] Compound XXVII:5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylicAcid Methyl Ester.

[0306] Now referring to Scheme K, to Compound XXIII:thiophene-2,5-dicarboxylic acid monomethyl ester (923 mg, 4.96 mmol) inDMF (10 ml) was added 1-hydroxybenzotriazole (HOBT) ( 870 mg, 6.45 mmol)followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrocloride(EDC) (1.23 g, 6.45 mmol) and (1.2 ml, 10.9 mmol) of NMM. Compound XXIV:N,N′-Bis-(Boc)-N″-(2-Amino-ethyl)-guanidine (6.45 mmol, 1.96 g) was thenadded in DMF(10 ml) to the reaction mixture which was then left to stirat room temperature for 16 hours. Solvent was evaporated and the residuewas thrown in a 10% citric acid solution (50 ml) and extracted withETOAC (3×70 ml). The organic phases were combined and washed with asaturated solution of NaHCO₃ followed by a solution of Brine, dried overMgSO₄ and evaporated. The crude residue was then purified by flashcolumn chromatography using CH₂Cl₂/MeOH (10:0.2) to give the desiredproduct (Compound XXVII) in 94% yield. ¹H NMR (CDCl₃, 400 MHz) δ1.1-1.34 (m, 21H), 3.41-3.81 (m, 4H), 3.88 (s, 3H), 5.58-5.59 (d, 1H),7.69-7.70 (d, 1H), 8.43-8.54 (broad s, 1H), 8.70-8.88 (m, 1H).

[0307] Compound XXVIII:5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylicAcid.

[0308] With continued reference to Scheme K, To Compound XXVII:5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylicacid methyl ester (2.2 g, 4.66 mmol) in 50% THF/H₂O (50 ml) was added1.5 eq. of LiOH (294 mg, 6.99 mmol) and the reaction mixture was left tostir at room temperature for 3 hours. 10% citric acid solution was addeduntil acidic pH and THF was evaporated. The aqueous solution was thenextracted with CH₂Cl₂ (3×70 ml). The organic phases were combined andwashed with a solution of Brine, dried over MgSO₄ and evaporated to givethe desired product in 84% yield. ¹H NMR (CD₃OD, 400 MHz) δ 1.34-1.66(m, 21H), 3.49-3.67 (m, 4H), 7.61-7.70 (dd, 2H).

[0309] Compound XXXIX:3-{[5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicAcid Methyl Ester.

[0310] With continued reference to Scheme K, a solution of CompoundXXVIII:5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylicacid (100 mg, 0.22 mmol), Compound XXVI:(3-Amino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester bishydrochloride salt (64 mg, 0.24 mmol), EDC (46 mg, 0.24 mmol), HOBt (32mg, 0.24 mmol) and N-methylmorpholine (96 μL, 0.88 mmol) in DMF (2 mL)was stirred at rt for 48 hrs. The solution was then concentrated todryness and the residue was purified by chromatography eluting with 2-5%MeOH in dichloromethane. The resulting product (Compound XXIX) isobtained as a white solid (100 mg, 74%) ¹H NMR (400 MHz, CDCl₃) δ:11.31(s, 1H), 8.92 (br s, 1H), 8.56 (br s, 1H), 8.36 (d, 2 H), 7.51 (d, 1H),7.43 (br s, 1H), 6.68 (t, 1H), 6.30 (br s , 1H), 4.88 (m, 1H), 4.05 (m,1H), 3.82 (s, 3H), 3.76 (m, 2H), 3.61 (m, 2H), 1.56 (s, 9H), 1.52 (s,9H)

[0311] Compound XXX:3-{[5-(2-guanidino-ethylcarbamoyl)-thiophene-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicAcid Bis Trifluoroacetic Acid Salt.

[0312] With continued reference to Scheme K, to a solution of CompoundXXIX:3-{[5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carbonyl]-amino}-2-(pyrimidin-2-ylamino)-propionicacid methyl ester (100 mg, 0.16 mmol) in THF/water (4:1, 5 mL) was addedlithium hydroxide monohydrate (10 mg, 0.24 mmol). The solution wasstirred for 2 hours at room temperature after which the reaction wascomplete. The reaction mixture was concentrated under vacuum and theresidue was acidified with 5% KHSO₄ solution. The mixture was thenextracted with chloroform (4×) and the organic extracts were then washedwith brine, dried (Na₂SO₄) and concentrated to the free acid as a whitesolid. This solid was then stirred intrifluoroaceticacid/dichloromethane (1:1, 10 mL) for 2 hours. The reaction mixture wasconcentrated to dryness and the residue was triturated with ether. Theresulting solid Compound XXX was then dissolved in water, filtered andlyophilized to title compound as a white solid (54 mg, 52w). ¹H NMR (400MHz, DMSO) δ: 8.79 (t, 1H), 8.78 (t, 1 H), 8.29 (d, 2H), 7.69 (s, 2H),7.52 (br t, 1H), 7.29 (d, 1H), 6.64 (t, 1H), 4.53 (q, 1H), 3.71 (t, 2H),3.37 (m, 2H), 3.30 (m, 2H).

[0313] Compound XXXI: [2-(1-Oxy-pyridin-2-ylamino)-ethyl)]-carbamic AcidTert-butyl.

[0314] To a solution of (2-Amino-ethyl)-carbamic acid tert-butyl ester(130 mg, 0.85 mmol) in n-butanol (40 mL) was added a mixture of2-chloropyridine N-oxide (142 mg, 0.86 mmol) and DIEA (0.31 mL, 1.8mmol). The reaction mixture was refluxed at 110° C. for 14 hrs. Thesolvent was evaporated and the residue was purified on silica gel using30% Methanol/EtOAc as eluent, This gave 190 mg (91%) of pure[2-(1-Oxy-pyridin-2-ylamino)-ethyl)]-carbamic acid tert-butyl. ¹HNMR(300 MHz, CD₃OD) δ: 2.44(s, 9H), 3.30 (t, 2H), 3.50 (t, 2H), 6.77(t,1H), 7.02(m, 1H), 8.10(d, 1H), 8.55 (m, 1H).

[0315] Compound XXXII: [2-(Pyridin-2-ylamino)-ethyl]-carbamic AcidTert-butyl Ester.

[0316] To a solution of [2-(1-Oxy-pyridin-2-ylamino)-ethyl)]-carbamicacid tert-butyl (90 mg, 0.36 mmol) in methanol (25 mL) was addedammonium formate (25 mg, 0.37 mmol) and Pd/C under a stream of nitrogen.The reaction mixture was stirred overnight. The catalyst was filteredand the solvent was evaporated under reduced pressure. The residue waspurified on silica gel using 10% Methanol/EtOAc as eluant. This gave 42mg (50%) of pure [2-(Pyridin-2-ylamino)-ethyl]-carbamic acid tert-butylester. ¹HNMR (300 MHz, CDCl₃) δ: 2.43(s, 9H), 3.40 (m, 2H), 3.48 (m,2H), 6.42(d, 1H), 6.60(t, 1H), 7.42(t, 1H), 8.08 (bs, 1H).

[0317] Compound XXXIII:5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic AcidMethyl Ester.

[0318] To a solution of [2-(Pyridin-2-ylamino)-ethyl]-carbamic acidtert-butyl ester (44 mg, 0.14 mmol) was mixed with a mixture of(1:1)TFA/CH₂Cl₂ (30 mL) and the reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated and the residue wastritured with dry ether (2×30 mL). This gave 35 mg (95%) of puretrifluoroacetate salt. The salt was neutralized with DIEA and treatedwith mono methylthiophene dicarboxylic acid (32 mg, 0.17 mmol),hydroxybenzotriazole (24 mg, 0.17 mmol) in DMF (20 mL). To this mixturewas added 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride(33 mg, 0.17 mmol). The reaction was stirred overnight at roomtemperature. Insolubles were removed by filtration and the solvent wasevaporated. Purification of the residue on silica gel (5% MeOH/EtOAc)gave 38 mg (88%) of pure5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic acidmethyl ester. ¹HNMR (300 MHz, CDCl₃) δ: 3.43 (m, 2H), 3.51 (m, 2H), 3.92(s, 3H), 6.45(d, 1H) 6.80(t, 1H), 7.42(t, 1H), 7.45 (s, 1H), 7.55 (s,1H), 8.10 (s, 1H).

[0319] Compound XXXIV:3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicAcid Methyl Ester.

[0320] 5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylicacid methyl ester was hydrolyzed with LiOH as described before. To amixture of5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic acid (38mg, 0.12 mmol), salt of3-amino-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid2-tert-butoxycarbonylamino-ethyl ester (47 mg, 0.14 mmol),hydroxybenzotriazole (21 mg, 0.15 mmol) in DMF (20 mL), was added1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (29 mg,0.15 mmol). The reaction was stirred overnight at room temperature.Insolubles were removed by filtration and the solvent was evaporated.Purification of the residue on silica gel (10% MeOH/EtOAc) gave 60 mg(87%) of pure3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid methyl ester.

[0321]¹HNMR (300 MHz, CDCl₃) δ: 2.22 (s, 3H), 2.61 (s, 6H), 3.55 (m,4H), 3.82 (m, 1H), 4.09 (m, 1H), 6.50(d, 1H), 6.69(t, 1H), 6.90(s, 2H),7.05(t, 1H), 7.40(m, 3H), 8.10 (s, 1H), 8.43(m, 1H).

[0322] Compound XXXV:3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicAcid Acetic Acid Salt.

[0323] A mixture of3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid methyl ester (40 mg, 0.069 mmol), lithium hydroxide (34 mg, 1.39mmol), in acetonitrile (10 mL) was stirred for 4 hrs at roomtemperature. The solvent was removed and the crude reaction product wastaken up in ethyl acetate (40 mL). The solution was neutralized withacetic acid (1.0 mL). Solvent was than dried over sodium sulfate andevaporated. Purification of the residue on silica gel (10% MeOH-EtOAc)gave 40 mg of pure acetic acid salt of3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionicacid (86%). ¹HNMR (300 MHz, CD₃OD) δ: 2.22 (s, 3H), 2.61 (s, 6H), 3.57(m, 4H), 3.82 (m, 2H), 6.50(d, 1H), 6.69(m, 2H), 6.90(s, 2H), 7.42(m,3H), 8.01 (m, 1H).

[0324] Compound XXXVI:2-Benzenesulfonylamino-3-({5-[(1H-benzoimidazol-2-ylmethyl)-carbamoyl]-thiophene-2-carbonyl-amino)-propionic Acid.

[0325] compound I (4.79 g, 10.54 mmol) in dry DMA (20 mL) was treatedwith BOP at room temperature under N2. After 1h,2-aminomethylbenzimidazole dihydrochloride and NMI (2.5 mL, 31.6 mmol)in DMA (25 mL) were added and the reaction mixture was stirred at roomtemperature for 16h. DMA was removed under reduced pressure and theresidue was extracted with ethyl acetate and the organic extracts werewashed with H₂O and saturated NaHCO₃, dried over MgSO₄, filtered andconcentated. The crude material was purified by chromatography on flashSilica eluting with CH₂Cl₂ to 5% MeOH/CH₂Cl₂ to give 5.23 g of thet-butyl ester (52% yield). ¹H-NMR (400 MHz, DMSO-d₆): 9.34 (t, 1H), 8.70(t, 1H), 8.40 (d, 1H), 7.78 (m, 3H), 7.58 (m, 6H), 7.14 (m, 2H), 4.67(d, 2H), 4.03 (m, 2H), 3.40 (m, 1H), 1.12 (s, 9H).

[0326] The t-butyl ester (3.73 g) was treated with 50% TFA/CH₂Cl₂ (40mL) and the progress of the reaction was followed by TLC. After 3h, thereaction mixture was taken to dryness under reduced pressure and theresidue was triturated from ether then recrystalised from methanol/etherto give 2.24 g of compound XXXVI (58% yield). ¹H-NMR (400 MHz,CD₃-OD):7.85-7.44 (m, 11H), 5.04 (s, 2H), 4.21 (m, 1H), 3.74 (m, 1H), 3.49 (m,1H).

[0327] Compound XXXVII:3-({5-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-2-benzenesulfonylamino-propionicAcid Tert-butyl Ester.

[0328] HATU (200 mg, 0.52 mmol) was added in one portion at roomtemperature to a solution of5-(2-Benzenesulfonylamino-2-tert-butoxycarbonyl-ethylcarbamoyl)-thiophene-2-carboxylicacid (200 mg, 0.42 mmol) dissolved in anhydrous DMF with5-Aminomethyl-pyridin-2-ylamine (Dong-Mei Feng et al.; J. Med. Chem.(1997), 40, 3726) (200.0 mg, 1.63 mmol) and triethyl amine (200 μl).This reaction mixture was left stirring at room temperature for 12 hoursthen the DMF was evaporated and the residue was purified via flashchromatography on silica gel using first ethyl acetate to flush-outundesired material then methanol:ethyl acetate (1:4) to give compoundXXXVII as a pure yellow solid after evaporation of the solvent. (HNMR,400 MHz, CD3OD) δ: 7.98 (d, 1H), 7.80 (m, 2H), 7.56-7.43 (m, 7H), 7.32(m, 1H), 6.50 (d, 2H), 4.90 (bs, 2H), 4.36 (d, 2H), 4.09-4.03 (m, 1H),3.60 (m, 1H), 3.52 (m, 1H), 1.25 (s, 9H).

[0329] Compound XXXVIII:3-({5-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-2-benzenesulfonylamino-propionicAcid Trifluoroacetic Acid Salt.

[0330] Compound XXXVII (30 mg, 0.053 mmol) was dissolved indichloromethane (2.0 mL) then at room temperature trifluoroacetic acidwas added to this solution which was then left stirring over nigth.Evaporation of the solvents followed by trituration of the resultingresidue with anhydrous diethyl ether filtration gave a solid which waswashed twice with dichloromethane then dried under vaccuum to give 28 mgof compound XXXVII as a beige powder.

[0331] (HNMR, 400 MHz, CD3OD) δ: 7.97 (dd, 1H), 7.84 (m, 3H), 7.64 (d,1H), 7.58 (d, 1H), 7.53-7.44 (m, 3H), 7.03 (d, 1H), 4.45 (s, 2H), 4.18(dd, 1H), 3.74 (dd, 1H), 3.49 (dd, 1H)

[0332] Compound XXXIX: [2-(Pyrimidin-2-ylamino)-ethyl 3-carbamicAcid-tert-butyl Ester.

[0333] (2-Amino-ethyl)-carbamic acid tert-butyl ester (2.0 g, 0.013 mol)was haled 12 hours between 65-75 C along with chloropyrimidine (1.0 g,2.25 mmol) and diisopropyl ethyl amine (1.5 mL) in anhydroustetrahydrofuran (1.0 mL). The reaction mixture was concentrated and theresulting residue was purified on silica gel using a ethyl acetate,hexane (1:1) mixture of eluent providing 1.5 g compound XXXIX as a whitepowder. HNMR (400 MHz, CDCl₃) δ: 8.35 (m, 2H), 6.59 (t, 1H), 5.81 (bs,1H), 5.12 (bs, 1H), 3.58 (m, 2H), 3.38 (m, 2H), 1,45 (s, 9H).

[0334] Compound XL: N,1-Pyrimidin-2-yl-ethane-1,2-diamineTrifluoroacetic Acid Salt.

[0335] 2-(Pyrimidin-2-ylamino)-ethyl]-carbamic acid-tert-butyl ester(900 mg, 3.8 mmol) was dissolved in anhydrous dichloromethane (5.0 mL),trifluoroacetic acid (5.0 mL) was added to the mixture which was thenleft stirring at room temperature for 12 hours. The solvents wereevaporated under reduced pressure and the resulting yellow oil was mixedwith anhydrous diethyl ether, the ether layer was separated thendiscarded and the yellow oil was left under vaccum to crystallizeproviding 1.08 g of compound XL as a yellow powder. HNMR (400 MHz, DMSO,d6) δ: 8.35 (m, 2H), 7.86 (bs, 3H), 7.39 (bs, 1H), 6.68 (t, 1H), 3.52(m, 2H), 3.00 (m, 2H).

[0336] Compound XLI:2-Benzenesulfonylamino-3-({5-[2-(pyrimidin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-propionicAcid Tert-butyl Ester.

[0337] HATU (241.7 mg, 0.636 mmol) was added in one portion at roomtemperature to a solution of5-(2-Benzenesulfonyl-amino-2-tert-butoxycarbonyl-ethylcarbamoyl)-thiophene-2-carboxylicacid (200 mg, 0.424 mmol) dissolved in anhydrous DMF (5.0 mL) withN,1-Pyrimidin-2-yl-ethane-1,2-diamine trifluoroacetic acid salt(Dong-Mei Feng et al.; J. Med. Chem. (1997), 40, 3726) (232 mg, 0.636mmol) and diisopropylethylamine (500 μL). This reaction mixture was leftstirring at room temperature for 1 hour then water was added and thismixture was extracted with ethyl acetate, the organic phase wasseparated dried (Na₂SO₄), filtered, then concentrated and the resultingresidue was purified via flash chromatography on silica gel using firstethyl acetate to flush-out undesired material then methanol:ethylacetate (1:9) to compound XLI as a pure white powder after evaporationof the solvent. (HNMR, 400 MHz, DMSO, d6) δ: 8.72 (m, 1H), 8.68 (m, 1H),8.39 (d, 1H), 8.27 (d, 2H), 7.77 (m, 2H), 7,67 (d, 1H), 7.62-7.51 (m,4H), 7.23 (m, 1H), 6.58 (t, 1H), 4.03 (m, 1H), 3.42 (m, 6H), 1.12 (s,9H).

[0338] Compound XLII:2-Benzenesulfonylamino-3-({5-[2-(pyrimidin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-propionicAcid Trifluoroacetic Acid Salt.

[0339] Compound XLI (160 mg, 0.278 mmol) was dissolved in anhydrousdichloromethane (2 mL). To this solution at room temperature was addedtrifluoroacetic acid and the reaction mixture was then stirred 12 hours.The reaction mixture was then concentrated under reduced pressure, theresulting residue was triturated in anhydrous diethyl ether then driedunder vaccuum to give 200 mg of compound XLII contaminated with thesolvent as a yellow oil. (HNMR, 400 MHz, DMSO, d6) δ: 8.73 (m, 1H), 8.62(m, 1H), 8.35 (bs, 2H), 8.25 (d, 1H), 7.75 (m, 2H), 7.67-7.45 (m, 5H),6.67 (m, 1H), 4.02 (m, 1H), 3.51-3.28 (m, 6H).

[0340] Compound XLIII:2-Benzenesulfonylamino-3-({5-[2-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-propionicacid, hydrochloride salt.

[0341] Compound XLII (200 mg, 0.316 mmol) was dissolved in acetic acid(10 mL) and hydrochloric acid (0.1 mL) then palladium on carbon 10% (200mg) and the reaction mixture was pressurized with hydrogen (45-50 psi),stirred vigorously for 2 hours then the solution was filtered on celite.The solvents were evaporated under reduced pressure and the resultingresidue was triturated in anhydrous diethyl ether and this white powderwas purified on C8 Bond elute reverse phase using 10% acetonitrile inwater as the eluent to provide 25 mg of material which was lyophilizedin diluted hydrochloric acid providing 25 mg of compound XLIII as awhite powder.

[0342] (HNMR, 400 MHz, CD₃OD) δ: 7.84 (dd, 1H), 7.65 (d, 1H), 7.59 (d,1H), 7.54-7.45 (m, 3H), 4.21 (dd, 1H), 3.75 (dd, 1H), 3.55-3.45 (m, 3H),3.38 (t, 6H), 1.96 (m, 2H).

EXAMPLE 2 Fibrinogen Binding to Immobilized GP IIb-IIIa (α_(IIb)β₃) andα_(v)β₃.

[0343] The wells of plastic microtiter plates were coated overnight at4° C. with purified active α_(IIb)β₃ (Calbiochem) or placental α_(v)β₃at 0.5 ug/mL (100 uL/well) in a buffer containing 150 mM NaCl, 20 mMTris, pH 7.4, 1 mM MgCl₂, 0.2 mM MnCl₂, and including 1 mM CaCl₂ forα_(IIb)β₃. Blocking of nonspecific sites was achieved by incubating thewells with 35 mg/mL bovine serum albumin (BSA) for at least 2 hours at37° C. Biotinylated-fibrinogen (10 nM) was added in 0.2 mL bindingbuffer (100 mM NaCl, 50 mM Tris, pH 7.4, 1 mM MgCl₂, 0.2 mM MnCl₂ and 1mg/mL BSA including 1 mM CaCl₂ for α_(IIb)β₃) to the wells in triplicatein the absence or presence of increasing concentrations of compounds ofinterest (0.001-100 uM) and further incubated for 2 hours at 37° C.Nonbound fibrinogen was removed by five washes with binding buffer.Avidin conjugated to alkaline phosphatase (Sigma), diluted in bindingbuffer, was added and incubated for two hours at 37° C. The plates werewashed five times with binding buffer, and after addition of thesubstrate PNPP (Pierce), the enzyme activity was measured by theabsorbance at 405 nm. The concentration of inhibitor required to inhibit500 of biotinylated-fibrinogen binding was defined as IC₅₀ determined bya nonlinear, sigmoidal dose response variable slope from the GraphPadPrism software. The results of the α_(v)β₃ and α_(IIb)β₃ assays arereported in Table 1. TABLE 1 IC₅₀ values for the fibrinogen bindingassay. IC₅₀ IC₅₀ α_(v)β₃ α_(IIb)β₃ CMPD # Structure (μM) (μM) VII

6.6 13.7 VIII

3.2 5.9 XI

.00058 .00031 XXI

0.045 0.931 XXX

0.15 0.69

EXAMPLE 3 Cell Adhesion Assay.

[0344] The wells of 96-well plates (Immunolon) were coated, byincubation overnight at 4° C., with 5 ug/mL vitronectin, 2 ug/mLosteopontin, or fibronectin or 10 mg/mL BSA in PBS. The protein solutionwas flicked out and the wells were blocked with 10 mg/mL BSA (0.1 mL)for 1-2 hours at 37° C. Cells HT29, K562, or K562 transfected withα_(v)β₃ (Blystone et al., 1994) were loaded with a fluorescent marker,5-chloromethylfluorescein diacetate (Molecular Probes, Eugene, Oreg.)for 1 hour at 37° C., then incubated in fresh medium without thefluorescent marker for 1 hour. Cells were lifted with trypsin-EDTA andwashed two times with Hank's balanced salt solution minus cations(Sigma) supplemented with 1 mM MgCl₂ Cells (75,000 cells/well) wereadded to coated plates in triplicate and allowed to attach at 37° C. for1 hour in the presence or absence of specific antibodies (5 ug/mL) or10-fold dilutions of compounds of interest starting at 10 uM.Nonadherent cells were removed by gentle washing twice with PBS. Theadherent cells were solubilized with 1% triton x-100 and detected usinga fluorescence plate reader (DYNEX Technologies). The number of attachedcells was calculated based upon standard curves for each cell line usedin the experiment. Non-specific cell attachment (attachment to wellscoated with BSA) was always less than 5%. The results are presented inTable 2. TABLE 2 IC₅₀ values for the cell adhesion assay. IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) K562-tr HT29 K562 Osteopontin Vitronectin FibronectinCompound (α_(v)β₃) (α_(v)β₅) (α₅β₁) VII >10 >10 >10 X >10 >10 >10 XI0.087 0.21 5.3 XIX 1.3 12 >10 XXI 2.3 5.4 >10 XXX 3.4 >10 >10

Example 4 Cell Proliferation and Cytotoxicity MTT Assay

[0345] The wells of microtiter plates were seeded with 2000 cells/wellT24, 2500 cells/well HT29 or 5000 cells/well HMVEC (Cell Systems) in 100uL, followed by an overnight culture for cell adhesion. The next day,the media is supplemented with 100 uL of 10-fold dilution of compound ofinterest starting at 10 uM. Following culture for 72 hours,3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT;Sigma) at 2 mg/mL was added to each well (50 uL/well) and furtherincubated for 4 hours at 37° C. The medium was flicked out and 200 uL ofa 1:1 solution of ethanol:acetone followed by 25 uL of glycine buffer(0.1 M glycine, 0.1M NaCl, pH 10.5) is added and the color measured bythe absorbance at 570 nm. The results are presented in Table 3. TABLE 3Cytotoxicity Assay Compound number IC₅₀ (uM) HMVEC IC₅₀ (uM) HT29VII >10 >10 VIII >10 >10 XI 0.87 9.9 XXI 8.9 >10 XXX >10 >10

EXAMPLE 5 Chick Chorioallantoic Membrane (CAM)

[0346] A) Shell-Less Embryo Culture

[0347] Fertilized white leghorn chicken eggs (SPAFAS Inc., Norwich,Conn.) were received at day 0 and incubated for 3 days at 37 C withconstant humidity. On day 3, eggs were rinsed with 70% ethanol andopened into 100 mm² tissue culture coated Petri dishes under asepticconditions. The embryos were then returned to a humidified 38 Cincubator for 7-9 additional days.

[0348] B) Mesh Assay

[0349] Vitrogen (Collagen Biomaterials, Palo Alto, Calif.) at a finalconcentration of 0.73 mg/mL and Matrigel (Becton Dickinson, Bedford,Mass.) at a final concentration of 10 mg/mL was directly pipetted ontoNylon meshes with 250 μm² openings which were cut into 4 mm×4 mm squaresand autoclaved. Polymerization of meshes were under aseptic conditions,on bacteriological Petri dishes. The polymerization conditions for eachsubstrate were identical; after mixing with or without 250 μg ofVPF/VEGF₁₆₅ (Peprotech, Rocky Hill, N.J.) and/or compounds of interest,40 μL were pipetted onto each mesh in a bacteriological Petri dish. ThePetri dish was placed in a humidified 37 C incubator with 5% CO₂ for 30minutes to allow polymerization followed by an incubation at 4° C. for 2hours.

[0350] In a tissue culture enclosure, meshes were placed onto theperiphery of the CAM of a day 12-14 embryo, excluding areas containingmajor vessels. The embryos were then returned to the humidified 38° C.incubator with 3% CO₂ for 24 to 48 additional hours.

[0351] C) Visualization and Quantification of Vessels

[0352] Embryos were removed from the incubator and meshes were viewedunder a dissecting microscope for gross evaluation. Injection of 400 μLFITC dextran, MW 2,000,000 (Sigma, St. Louis, Mo.) through glassmicrocapillary tubes by infusion into the umbilical vein was performedat a rate of 200 μl per minute. The FITC dextran was allowed tocirculate for 5 minutes and 3.7% formaldehyde in PBS was applieddirectly on each mesh. The embryos were then incubated at 40° C. for 5minutes and the meshes were dissected off the CAM and fixed in 3.7%formaldehyde for 10 minutes to overnight.

[0353] After fixation, meshes were mounted on slides with 90% glycerolin PBS and visualized on an inverted fluorescence microscope. A NikonDiaphot with a Sony DXC-151A camera attached to the side port was usedfor capture of images and analysis was with the NIH Image 1.61 softwareprogram. For each mesh, 5 random staggered images (approximately 600 μmeach) were captured. The areas of high intensity were highlighted andmeasured. Results are expressed as ability to suppress capillaryformation after subtraction from negative control. Values werecalculated as a inhibition, considering 100% the capillary densityachieved by VPF in the presence of vitrogen alone minus the bakgroundlevels in the absence of VPF. Negative values indicated angiogenicstimulation above the VPF positive control. Results for the cam assayshowed significant inhibition values for the compounds tested. TABLE 4CAM Assay % of inhibition at 33 μg/mesh in Compound number the presenceof VEGF* VII 34% VIII 36% XI 38% XVIII 20% XIX  8% XXX 31% XXI 32%

EXAMPLE 6 Mouse Matrigel Angiogenesis Assay

[0354] To examine VEGF driven angiogenesis, cells expressing murine VEGF(SK-MEL2-V+) or vector alone (SK-MEL2) were collected by treatment ofculture flasks with trypsin, and resuspended to a concentration of 1×107cells in 0.6 mL in serum free media. The cell suspension was mixedgently with 1.4 mL Matrigel (Collaborative Biomedicals) and loaded insyringes. Alternatively, to examine FGF driven angiogenesis, matrigelwas mixed with 500 ng bFGF with 1U heparin. The matrigel suspensionswere injected into mice subcutaneously, 200 uL per injection, on eachside midway between the flank and the shoulder blades. Compounds ofinterest were injected at varying doses e.g., 1, 5 or 10 mg/kg/day.Animals were injected with 100 uL of the compound dissolved with sterilesaline, in the back of the neck.

[0355] Mice (5 animals/group) were anaesthesized with avertin after 4 to6 days of treatment, and a cardiac perfusion with FITC-dextran (M.W.2,000,000) was performed to label vessels in the matrigel plugs.Matrigel/skin were fixed in situ followed by whole mount cross sectionsand analyzed by confocal microscopy. For immunohistochemistry, thepellets were collected with the overlying skin and placed in Histoprep(10% formalin in PBS) for 2 hours and then transferred to PBS for 3-4hours followed by 70% ethanol and storage at 4° C. until processing forparrafin sections. Sections were examined by immunohistochemistry forvon Willebrand factor VIII and PECAM-1 using the appropriate antibodies.

EXAMPLE 7 Inhibition of Metastasis in Angiomouse/Metamouse Human LungCancer Model of H460

[0356] Male and female athymic BALB/c nude mice between 4 and 5 weeks ofage were used. The animals were bred and maintained in an HEPA-filteredenvironment with cages, food and bedding sterilized by autoclaving. Thebreeding pairs were obtained from the Charles River Laboratories(Wilmington, Mass.). The animal diets were obtained from Harlan Teklab(Madison, Wis.). Ampicillin (Sigma, St Louis, Mo.) 5.0% (v/v) was addedto the autoclaved drinking water.

[0357] Compound VII was tested and AGM-1470(chloroacetyl-(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-ylester carbamic acid) was used as a positive control.

[0358] The compounds were dissolved using PEG400 with heating andsonicatin. The solutions were then diluted with saline to obtain thedesired concentrations (30%/70%) and stored at −20° C.

[0359] Human non small-cell lung cancer cell line H460 with expressionof green fluorescent protein was obtained from the National CancerInstitute. The cells were transfected with vectors carrying the greenfluorescent protein (GFP) gene. The cell line was propagated bysubcutaneous implantation in nude mice.

[0360] Test animals were transplanted by surgical orthotopicimplantation (SOI) using fragments harvested from subcutaneaous tumorstock animals. The animals were anesthetized with isoflurane and thesurgical area was sterilized using iodine solution and alcohol. A leftthoracotomy was made along the 4^(th) intercostal space using a pair ofscissors. Two pieces of H460 tumor tissue of one cubic millimiter eachwere sutured to the left lung using an 8-0 nylon surgical suture. Thethorax was closed using a sterile 6-0 silk suture. A sterile 3-ccsyringe with a 25-gauge needle was used to remove the air and inflatethe lung. All surgical and animal manipulations and procedures wereconducted under HEPA-filtered laminar flow hoods.

[0361] Extra numbers of mice were transplanted to compensate forpostsurgical losses. The orthotopically transplanted animals used wereselected to establish groups of similar mean body weight. Groups foreach of the cohort conditions wre randomly chosen. The cohort wasgrouped as follows. A total of 10 mice were used for each dosageregimen. Administration of test compounds and vehicle by subcutaneousinjection was begun three days after the orthotopic implantation. TABLE5 Study design for the inhibition of metastasis in angiomouse/metamousehuman lung cancer model of H460. Group Compound Dose Route Schedule Avehicle  0.1 SC 2 times/day mL/mouse B AGM-1470 10 mg/kg SC 3 times/weekC VII  5 mg/kg SC 2 times/day D VII 50 mg/kg SC 2 times/day

[0362] Two animals for each treatment group were sacrificed at day-14after orthotopic implantation of H460. The remaining animals for eachgroup were sacrificed at day-28 after implantation. The sacrificedanimals were evaluated for primary and secondary tumors. Grossexamination for distant metastasis was conducted at necropsy. Tissuesamples of the primary tumor and those from relevant organs such as thelung, the liver and the lymph nodes wre processed through standardsprocedures of hematoxylin and eosin staining for subsequent microscopicexamination.

[0363] The mediastinal lymph nodes, the liver and the lung in eachanimal were collected. The sampled tissues were sectioned and stained,then microscopically examined. The fisher-exact test was performed tocompare distant metastasis to these organs in the treated and thecontrols. Group D had no lung metastasis. The results are shown below.TABLE 6 Efficacy of compounds on metastasis. No. of animals Incidenceavailable of lymph Incidence for node P-value vs of lung P-value vs Grpathology metastasis control metastasis control A 9 3/9  — 5/9  — B 101/10 0.303 3/10 0.370 C 10 2/10 0.608 1/10 0.057 D 10 3/10 1 0/10 0.011

[0364] While particular embodiments of the invention have beendescribed, it will also be apparant to these of ordinary skill in theart that various modifications, including the preparation of certainanalogs, can be made without departing from the spirit and scope of theinvention. Accordingly, it is not intended that the invention be limitedexcept by the appended claims.

We claim:
 1. A compound of the formula:

wherein X is selected from the group comprising O and S; wherein A₁ andA₂ are individually selected from the group comprising O, S and N;wherein G₁ and G₃ are C₁₋₄ alkyl chains; wherein G₈ is a C₀₋₄ alkylchain; wherein G₂ is selected from the group comprising:

or H, wherein A₃ and A₄ are individually selected from the groupcomprising O, N, or S, and G₈ is a C₁₋₄ alkyl chain; wherein G₄ is aC₅₋₈ aryl, a C₅₋₈ arylsulfonylamino, an C₅₋₈ arylamino; and wherein G₆and G₇ are individually selected from the group comprising H, F, Cl, I,Br and a C₁₋₄ alkyl.
 2. The compound of claim 1, wherein X is S.
 3. Thecompound of claim 1, wherein X is O.
 4. The compound of claim 1, whereinA₁ is N.
 5. The compound of claim 1, wherein A₁ is O.
 6. The compound ofclaim 1, wherein A₂ is N.
 7. The compound of claim 1, wherein A₂ is O.8. The compound of claim 1, wherein G₁ is a C₁ alkyl.
 9. The compound ofclaim 1, wherein G₁ is —(CH₂)₀—.
 10. The compound of claim 1, wherein G₁is a C₂ alkyl.
 11. The compound of claim 1, wherein G₁ is a C₃ alkyl.12. The compound of claim 1, wherein G₃ is a C₁ alkyl.
 13. The compoundof claim 1, wherein G₃ is a C₂ alkyl.
 14. The compound of claim 1,wherein G₈ is a C₁ alkyl.
 15. The compound of claim 1, wherein G₅ is aC₂ alkyl.
 16. The compound of claim 1, wherein G₂ is represented by theformula:

or H, wherein A₃ is selected from the group comprising O, S and N and A₄is N.
 17. The compound of claim 1, wherein G₂ is represented by theformula:

or H, wherein A₃ and A₄ are individually selected from the groupcomprising N or O and G₈ is a C₂₋₃ alkyl chain.
 18. The compound ofclaim 1, wherein —N—G₂ forms a guanidino containing moiety.
 19. Thecompound of claim 1, wherein —N—G₂ forms a urea containing moiety. 20.The compound of claim 1, wherein —N—G₂ forms a cyclic guanidinocontaining moiety.
 21. The compound of claim 1, wherein —N—G₂ forms acyclic urea containing moiety.
 22. The compound of claim 1, wherein G₄is phenylsulfonylamino.
 23. The compound of claim 1, wherein G₄ isphenyl.
 24. The compound of claim 1, wherein G₆ and G₇ are halogens. 25.The compound of claim 1, wherein G₆ and G₇ are the same.
 26. Thecompound of claim 1, wherein G₆ or G₇ are F.
 27. The compound of claim 1further represented by the formula:

wherein X is selected from the group comprising O and S; A₁ and A₂ areindividually selected from the group comprising O, S and N; G₁ and G₃are C₁₋₄ alkyl chains; G₂ is selected from the group comprising:

or H, wherein A₃ and A₄ are individually selected from the groupcomprising O, N, or S, and G₈ is a C₁₋₄ alkyl chain; wherein G₄ is aC₅₋₈ aryl, a C₅₋₈ arylsulfonylamino, or a C₅₋₈ arylamino; and wherein G₆and G₇ are individually selected from the group comprising H, F, Cl, I,Br and a C₁₋₄ alkyl.
 28. The compound of claim 26, wherein X is S. 29.The compound of claim 26, wherein X is O.
 30. The compound of claim 26,wherein G₁ is a C₁ alkyl.
 31. The compound of claim 26, wherein G₁ is aC₂ alkyl.
 32. The compound of claim 26, wherein G₃ is a C₁ alkyl. 33.The compound of claim 26, wherein G₃ is a C₂ alkyl.
 34. The compound ofclaim 26, wherein G₂ is represented by the formula:

or H. wherein A₃ is selected from the group comprising O, S and N and A₄is N.
 35. The compound of claim 26, wherein G₂ is represented by theformula:

or H, wherein A₃ and A₄ are individually selected from the groupcomprising N or O and G₈ is a C₂₋₃ alkyl chain.
 36. The compound ofclaim 26, wherein —N—G₂ forms a guanidino containing moiety.
 37. Thecompound of claim 26, wherein —N—G₂ forms a urea containing moiety. 38.The compound of claim 26, wherein —N—G₂ forms is a cyclic guanidinocontaining moiety.
 39. The compound of claim 26, wherein —N—G₂ forms acyclic urea containing moiety.
 40. The compound of claim 26, wherein G₄is phenylsulfonylamino.
 41. The compound of claim 26, wherein G₄ isphenyl.
 42. A method of treating cancer comprising administering apharmaceutically effective amount of the compound of claim 1 to apatient.
 43. A method of treating a tumor comprising administering apharmaceutically effective amount of the compound of claim 1 to apatient.
 44. A method of treating a solid tumor comprising administeringa pharmaceutically effective amount of the compound of claim 1 to apatient.
 45. A method of treating metastasis comprising administering apharmaceutically effective amount of the compound of claim 1 to apatient.
 46. A method of inhibiting angiogenesis comprisingadministering a pharmaceutically effective amount of the compound ofclaim 1 to a patient.
 47. A method of inhibiting fibronectin bindingcomprising administering a pharmaceutically effective amount of thecompound of claim 1 to a patient.
 48. A method of inhibiting osteopontinbinding comprising administering a pharmaceutically effective amount ofthe compound of claim 1 to a patient.
 49. A method of treating foot andmouth disease comprising administering a pharmaceutically effectiveamount of the compound of claim 1 to a patient.
 50. A method of treatingosteoporosis comprising administering a pharmaceutically effectiveamount of the compound of claim 1 to a patient.
 51. A method of treatingrestenosis comprising administering a pharmaceutically effective amountof the compound of claim 1 to a patient.
 52. A method of treating oculardiseases comprising administering a pharmaceutically effective amount ofthe compound of claim 1 to a patient.
 53. A method of treating heartdiseases comprising administering a pharmaceutically effective amount ofthe compound of claim 1 to a patient.
 54. A method of treating arthritiscomprising administering a pharmaceutically effective amount of thecompound of claim 1 to a patient.
 55. A method of treating diseases inwhich abnormal neovascularization occurs comprising administering apharmaceutically effective amount of the compound of claim 1 to apatient.
 56. A method of inhibiting α_(v) integrins comprisingadministering a pharmaceutically effective amount of the compound ofclaim 1 to a patient.
 57. A method of inhibiting α_(v)β₃ integrincomprising administering a pharmaceutically effective amount of thecompound of claim 1 to a patient.
 58. A pharmaceutical composition fortreating cancer comprising a pharmaceutically effective amount of acompound of claim
 1. 59. A pharmaceutical composition for treating tumorcomprising a pharmaceutically effective amount of a compound of claim 1.60. A pharmaceutical composition for treating solid tumor comprising apharmaceutically effective amount of a compound of claim
 1. 61. Apharmaceutical composition for treating metastasis comprising apharmaceutically effective amount of a compound of claim
 1. 62. Apharmaceutical composition for inhibiting angiogenesis comprising apharmaceutically effective amount of a compound of claim
 1. 63. Apharmaceutical composition for inhibiting fibronectin binding comprisinga pharmaceutically effective amount of a compound of claim
 1. 64. Apharmaceutical composition for inhibiting osteopontin binding comprisinga pharmaceutically effective amount of a compound of claim
 1. 65. Apharmaceutical composition for treating foot and mouth diseasecomprising a pharmaceutically effective amount of a compound of claim 1.66. A pharmaceutical composition for treating osteoporosis comprising apharmaceutically effective amount of a compound of claim
 1. 67. Apharmaceutical composition for treating restenosis comprising apharmaceutically effective amount of a compound of claim
 1. 68. Apharmaceutical composition for treating ocular diseases comprising apharmaceutically effective amount of a compound of claim
 1. 69. Apharmaceutical composition for treating heart diseases comprising apharmaceutically effective amount of a compound of claim
 1. 70. Apharmaceutical composition for treating arthritis comprising apharmaceutically effective amount of a compound of claim
 1. 71. Apharmaceutical composition for treating diseases in which abnormalneovascularization occurs comprising a pharmaceutically effective amountof a compound of claim
 1. 72. A pharmaceutical composition forinhibiting α_(v) integrins comprising a pharmaceutically effectiveamount of a compound of claim
 1. 73. A pharmaceutical composition forinhibiting α_(v)β₃ integrin comprising a pharmaceutically effectiveamount of a compound of claim
 1. 74. A combination useful for thetreatment of cancer comprising at least one compound of claim 1 with atleast one other anticancer agent or antiangiogenic agent.
 75. Acombination useful for the treatment of cancer comprising at least onecompound of claim 1 with at least one other anticancer agent selectedfrom the group consisting of alkylating agents, antitumor antibiotics,antimetabolites, biological agents, hormonal agents, nitrogen mustardderivatives and plant alkaloids.